Integrin receptor antagonists

ABSTRACT

This invention relates to novel fused heterocycles which are useful as antagonists of the alphavbeta3 and related integrin receptors, to pharmaceutical compositions containing such compounds, processes for preparing such compounds, and to methods of using these compounds, alone or in combination with other therapeutic agents, for the inhibition of cell adhesion, the treatment of angiogenic disorders, inflammation, bone degradation, cancer metastasis, diabetic retinopathy, thrombosis, restenosis, macular degeneration, and other conditions mediated by cell adhesion and/or cell migration and/or angiogenesis.

This is a division of U.S. application Ser. No. 08/980,016, filed Nov.26, 1997, U.S. Pat. No. 6,130,230, which claims the benefit of U.S.Provisional Application Ser. No.60/033,208, filed Nov. 27, 1996.

FIELD OF THE INVENTION

This invention relates to novel fused heterocycles which are useful asantagonists of the α_(v)β₃ and related integrin receptors, topharmaceutical compositions containing such compounds, processes forpreparing such compounds, and to methods of using these compounds, aloneor in combination with other therapeutic agents, for the inhibition ofcell adhesion and the treatment of angiogenic disorders, inflammation,bone degradation, tumors, metastases, thrombosis, and other cellaggregation-related conditions.

BACKGROUND OF THE INVENTION

Angiogenesis or neovascularization is critical for normal physiologicalprocesses such as embryonic development and wound repair (Folkman andShing, J. Biol. Chem. 1992, 267:10931-10934; D'Amore and Thompson, Ann.Rev. Physiol. 1987, 49:453-464). However, angiogenesis occurspathologically, for example, in ocular neovascularization (leading todiabetic retinopathy, neovascular glaucoma, retinal vein occlusion andblindness), in rheumatoid arthritis and in solid tumors (Folkman andShing, J. Biol. Chem., 1992, 267:10931-10934; Blood and Zetter, Biochim.Biophys. Acta 1990, 1032:118-128).

Tumor dissemination, or metastasis, involves several distinct andcomplementary components, including the penetration and transversion oftumor cells through basement membranes and the establishment ofself-sustaining tumor foci in diverse organ systems. To this end, thedevelopment and proliferation of new blood vessels, or angiogenesis, iscritical to tumor survival. Without neovascularization, tumor cells lackthe nourishment to divide and will not be able to leave the primarytumor site (Folkman and Shing, J. Biol. Chem. 1992, 267:10931-10934).

Inhibition of angiogenesis in animal models of cancer has been shown toresult in tumor growth suppression and prevention of metastatic growth(Herblin et al., Exp. Opin. Ther. Patents. 1994, 1-14). Many angiogenicinhibitors have been directed toward blocking initial cytokine-dependentinduction of new vessel growth, e.g. antibodies to endothelial cellgrowth factors. However, these approaches are problematic because tumorand inflammatory cells can secrete multiple activators of angiogenesis(Brooks, et al., Cell 1994, 79:1157-1164). Therefore, a more generalapproach that would allow inhibition of angiogenesis due to a variety ofstimuli would be of benefit.

The integrin α_(v)β₃ is preferentially expressed on angiogenic bloodvessels in chick and man (Brooks, et al., Science 1994, 264:569-571;Enenstein and Kramer, J. Invest. Dermatol. 1994, 103:381-386). Integrinα_(v)β₃ is the most promiscuous member of the integrin family, allowingendothelial cells to interact with a wide variety of extracellularmatrix components (Hynes, Cell 1992, 69:11-25). These adhesiveinteractions are considered to be critical for angiogenesis sincevascular cells must ultimately be capable of invading virtually alltissues.

While integrin α_(v)β₃ promotes adhesive events important forangiogenesis, this receptor also transmits signals from theextracellular environment to the intracellular compartment (Leavesley,et al., J. Cell Biol. 1993, 121:163-170, 1993). For example, theinteraction between the α_(v)β₃ integrin and extracellular matrixcomponents promotes a calcium signal required for cell motility.

During endothelium injury, the basement membrane zones of blood vesselsexpress several adhesive proteins, including but not limited to vonWillebrand factor, fibronectin, and fibrin. Additionally, severalmembers of the integrin family of adhesion receptors are expressed onthe surface of endothelial, smooth muscle and on other circulatingcells. Among these integrins is α_(v)β₃, the endothelial cell,fibroblast, and smooth muscle cell receptor for adhesive proteinsincluding von Willebrand factor, fibrinogen (fibrin), vitronectin,thrombospondin, and osteopontin. These integrins initiate acalcium-dependent signaling pathway that can lead to endothelial cell,smooth muscle cell migration and, therefore, may play a fundamental rolein vascular cell biology.

An antibody to the α_(v)β₃ integrin has been developed that inhibits theinteraction of this integrin with agonists such as vitronectin (Brooks,et al., Science 1994, 264:569-571). Application of this antibody hasbeen shown to disrupt ongoing angiogenesis on the chick chorioallantoicmembrane (CAM), leading to rapid regression of histologically distincthuman tumor transplanted onto the CAM (Brooks, et al., Cell 1994,79:1157-1164). In this model, antagonists of the α_(v)β₃ integrininduced apoptosis of the proliferating angiogenic vascular cells,leaving pre-existing quiescent blood vessels unaffected. Thus, α_(v)β₃integrin antagonists have been shown to inhibit angiogenesis. Based onthis property, therapeutic utility of such agents is expected in humandiseases such as cancer, rheumatoid arthritis and ocular vasculopathies(Folkman and Shing, J. Biol. Chem. 1992, 267:10931-10934).

Increasing numbers of other cell surface receptors have been identifiedwhich bind to extracellular matrix ligands or other cell adhesionligands thereby mediating cell-cell and cell-matrix adhesion processes.These receptors belong to a gene superfamily called integrins and arecomposed of heterodimeric transmembrane glycoproteins containing α- andβ-subunits. Integrin subfamilies contain a common β-subunit combinedwith different α-subunits to form adhesion receptors with uniquespecificity. The genes for eight distinct β-subunits have been clonedand sequenced to date.

Two members of the β₁ subfamily, α₄β₁ and α₅β₁ have been implicated invarious inflammatory processes. Antibodies to α4prevent adhesion oflymphocytes to synovial endothelial cells in vitro, a process which maybe of importance in rheumatoid arthritis (VanDinther-Janssen, et al., J.Immunol. 1991, 147:4207). Additional studies with monoclonalanti-α₄antibodies provide evidence that α₄β₁ may additionally have arole in allergy, asthma, and autoimmune disorders (Walsh, et al., J.Immunol. 1991, 146:3419; Bochner, et al., J. Exp. Med. 1991 173:1553;Yednock, et al., Nature 1992, 356:63). Anti-α4 antibodies also block themigration of leukocytes to the site of inflammation (Issedutz, et al.,J. Immunol. 1991, 147:4178).

The α_(v)β₃ heterodimer is a member of the β₃ integrin subfamily and hasbeen identified on platelets, endothelial cells, melanoma, smooth musclecells, and osteoclasts (Horton and Davies, J. Bone Min. Res. 1989,4:803-808; Davies, et al., J. Cell. Biol. 1989, 109:1817-1826; Horton,Int. J. Exp. Pathol. 1990, 71:741-759). Like GPIIb/IIIa, the vitronectinreceptor binds a variety of RGD-containing adhesive proteins such asvitronectin, fibronectin, VWF, fibrinogen, osteopontin, bone sialoprotein II and thrombospondin in a manner mediated by the RGD sequence.A key event in bone resorption is the adhesion of osteoclasts to thematrix of bone. Studies with monoclonal antibodies have implicated theα_(v)β₃ receptor in this process and suggest that a selective α_(v)β₃antagonist would have utility in blocking bone resorption (Horton, etal., J. Bone Miner. Res. 1993, 8:239-247; Helfrich, et al., J. BoneMiner. Res. 1992, 7:335-343).

PCT Patent Application WO 94/22835 discloses compounds having thegeneral formula:

(M¹)_(n)—Q—(M²)_(1−n)—L—A

European Patent Application Publication Number 614664 disclosescompounds having the general formula:

PCT Patent Application WO 94/29273 discloses compounds having thegeneral formula:

R, R*=carboxy bearing alkyl group

R⁶=amine bearing group

PCT Patent Application WO 96/18602 discloses compounds having thegeneral formula:

European Patent Application Publication Number EP 635492 disclosescompounds having the general formula:

PCT Patent Application WO 96/22288 discloses compounds having thegeneral formula:

None of the above references teaches or suggests the compounds of thepresent invention which are described in detail below.

SUMMARY OF THE INVENTION

The present invention provides novel compounds which bind to integrinreceptors thereby altering cell-matrix and cell-cell adhesion processes.The compounds of the present invention are useful for the treatment ofangiogenic disorders, inflammation, bone degradation, tumors,metastases, thrombosis, and other cell aggregation-related conditions ina mammal.

One aspect of this invention provides novel compounds of Formulae I-IV(described below) which are useful as antagonists of the α_(v)β₃receptor. The compounds of this invention inhibit the binding ofvitronectin to α_(v)β₃ and inhibit cell adhesion. This invention alsoincludes pharmaceutical compositions containing such compounds ofFormulae I-IV, and methods of their use for the inhibition ofangiogenesis, and/or for the treatment of angiogenic disorders.

The present invention also provides novel compounds, pharmaceuticalcompositions and methods which may be used in the treatment orprevention of diseases which involve cell adhesion processes, including,but not limited to, rheumatoid arthritis, asthma, allergies, adultrespiratory distress syndrome, graft versus host disease, organtransplantation, septic shock, psoriasis, eczema, contact dermatitis,osteoporosis, osteoarthritis, atherosclerosis, metastasis, woundhealing, diabetic retinopathy, ocular vasculopathies, thrombosis,inflammatory bowel disease and other autoimmune diseases.

Also included in this invention are pharmaceutical kits containingdosage units of a compound of Formulae I-IV, for the treatment of celladhesion related disorders, including, but not limited to, angiogenicdisorders.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides novel compounds of Formulae I-IV(described below) which bind to integrin receptors thereby alteringcell-matrix and cell-cell adhesion processes. The compounds of thisinvention are useful for the treatment of angiogenic disorders,inflammation, bone degradation, tumors, metastases, thrombosis, andother cell aggregation-related conditions in a mammal.

One aspect of this invention provides novel compounds of Formulae I-IV(described below) which are useful as antagonists of the α_(v)β₃receptor. The compounds of this invention inhibit the binding ofvitronectin to α_(v)β₃ and inhibit cell adhesion. This invention alsoincludes pharmaceutical compositions containing such compounds ofFormulae I-IV, and methods of using such compounds for the inhibition ofangiogenesis, and/or for the treatment of angiogenic disorders.

[1a] In a first embodiment the present invention comprises compounds ofFormula I:

including stereoisomeric forms thereof, or mixtures of stereoisomericforms thereof, or pharmaceutically acceptable salt or prodrug formsthereof wherein:

R¹ is selected from:

D is —N(R¹²)— or —S—;

J is —C(R²)— or —N—;

K, L and M are independently —C(R²)— or —C(R³)—;

R² and R³ are independently selected from:

H, C₁-C₄ alkoxy, NR¹¹R¹², halogen, NO₂, CN, CF₃, C₁-C₆ alkyl, C₃-C₆alkenyl, C₃-C₇ cycloalkyl, C₃-C₇ cycloalkyl(C₁-C₄ alkyl), aryl(C₁-C₆akyl)-, (C₁-C₆ alkyl)carbonyl, (C₁-C₆ alkoxy)carbonyl, arylcarbonyl, andaryl substituted with 0-4 R⁷,

alternatively, when R² and R³ are substituents on adjacent atoms, theycan be taken together with the carbon atoms to which they are attachedto form a 5-7 membered carbocyclic or 5-7 membered heterocyclic aromaticor nonaromatic ring system, said carbocyclic or heterocyclic ring beingsubstituted with 0-2 groups selected from C₁-C₄ alkyl, C₁-C₄ alkoxy,halo, cyano, amino, CF₃ and NO₂;

R^(2a) is selected from:

H, C₁-C₁₀ alkyl, C₂-C₆ alkenyl, C₃-C₁₁ cycloalkyl, C₃-C₇cycloalkyl(C₁-C₄ alkyl), aryl, aryl(C₁-C₄ alkyl)-, (C₂-C₇alkyl)carbonyl, arylcarbonyl, (C₂-C₁₀ alkoxy)carbonyl, C₃-C₇cycloalkoxycarbonyl, C₇-C₁₁ bicycloalkoxycarbonyl, aryloxycarbonyl,aryl(C₁-C₁₀ alkoxy)carbonyl, C₁-C₆ alkylcarbonyloxy(C₁-C₄alkoxy)carbonyl, arylcarbonyloxy(C₁-C₄ alkoxy)carbonyl, and C₃-C₇cycloalkylcarbonyloxy(C₁-C₄ alkoxy)carbonyl;

R⁴ is selected from:

H, C₁-C₁₀ alkyl, (C₁-C₁₀ alkyl)carbonyl, aryl, aryl(C₁-C₄ alkyl)-,C₃-C₁₁cycloalkyl, and C₃-C₁₁ cycloalkyl(C₁-C₄ alkyl)-;

U is selected from:

—(CH₂)_(n)—, —(CH₂)_(n)O(CH₂)_(m)—, —(CH₂)_(n)N(R¹²) (CH₂)_(m)—,—N(H)(CH₂)_(n)—, —(CH₂)_(n)C(═O)(CH₂)_(m)—,—(CH₂)_(n)S(O)_(p)(CH₂)_(m)—, —(CH₂)_(n)NHNH(CH₂)_(m)—, —N(R¹⁰)C(═O)—,—NHC(═O)(CH₂)_(n)—, —C(═O)N(R¹⁰)—, and —N(R¹⁰)S(O)_(p)—;

W is —C(═O)—N(R¹⁰)—(C₁-C₃ alkylene)-, in which the alkylene group issubstituted by R⁸ and by R⁹:

R⁸ and R⁹ are independently selected from:

H, CO₂R^(18b), C(═O)R^(18b), CONR¹⁷R^(18b)

hydroxy, C₅-C₁₀ alkoxy, nitro, —N(R¹⁰)R¹¹, —N(R¹⁶)R¹⁷, aryl(C₀-C₆alkyl)carbonyl, aryl(C₃-C₆ alkyl), heteroaryl(C₁-C₆ alkyl),CONR^(18a)R²⁰, SO₂R^(18a), SO₂NR^(18a)R²⁰,

C₁-C₁₀ alkyl substituted with 0-1 R⁶,

C₅-C₁₀ alkenyl substituted with 0-1 R⁶,

C₅-C₁₀ alkynyl substituted with 0-1 R⁶,

C₃-C₈ cycloalkyl substituted with 0-1 R⁶,

C₅-C₆ cycloalkenyl substituted with 0-1 R⁶,

C₁-C₁₀ alkylcarbonyl,

C₃-C₁₀ cycloalkyl(C₁-C₄ alkyl)-, phenyl substituted with 1-3 R⁶,

naphthyl substituted with 0-3 R⁶,

a 5-10 membered heterocyclic ring containing 1-3 N, O, or S heteroatoms,wherein said heterocyclic ring may be saturated, partially saturated, orfully unsaturated, said heterocyclic ring being substituted with 0-2 R⁷,and

C₅-C₁₀ alkyl substituted with 0-3 R⁷,

providing that any of the above alkyl, cycloalkyl, aryl or heteroarylgroups may be unsubstituted or substituted independently with 1-2 R⁷;

R⁶ is selected from:

H, C₁-C₁₀ alkyl, hydroxy, C₁-C₁₀ alkoxy, nitro, C₁-C₁₀ alkylcarbonyl,—N(R¹¹)R¹², cyano, halo, CF₃, CHO, CO₂R^(18b), C(═O)R^(18b),CONR¹⁷R^(18b), OC(═O)R¹⁰, OR¹⁰, OC(═O)NR¹⁰R¹¹, NR¹⁰C(═O)R¹⁰,NR¹⁰C(═O)OR²¹, NR¹⁰C(═O)NR¹⁰R¹¹, NR¹⁰SO₂NR¹⁰R¹¹, NR¹⁰SO₂R²¹,S(O)_(p)R¹¹, SO₂NR¹⁰R¹¹,

aryl substituted with 0-3 groups selected from halogen, C₁-C₆ alkoxy,C₁-C₆ alkyl, CF₃, S(O)_(m)Me, and —NMe₂,

aryl(C₁-C₄ alkyl)-, said aryl being substituted with 0-3 groups selectedfrom halogen, C₁-C₆ alkoxy, C₁-C₆ alkyl, CF₃, S(O)_(p)Me, and —NMe₂, and

a 5-10 membered heterocyclic ring containing 1-3 N, O, or S heteroatoms,wherein said heterocyclic ring may be saturated, partially saturated, orfully unsaturated, said heterocyclic ring being substituted with 0-2 R⁷;

R⁷ is selected from:

H, hydroxy, C₁-C₄ alkyl, C₁-C₄ alkoxy, aryl, aryl(C₁-C₄ alkyl)-, (C₁-C₄alkyl)carbonyl, CO₂R^(18a), SO₂R¹¹, SO₂NR¹⁰R¹¹, OR¹⁰, and N(R¹¹)R¹²;

R¹⁰ is selected from:

H, C₃-C₆ alkenyl, C₃-C₁₁ cycloalkyl, aryl, (C₃-C₁₁cycloalkyl)methyl,aryl(C₁-C₄ alkyl), and C₁-C₁₀ alkyl substituted with 0-2 R⁶;

R¹¹ is selected from:

H, hydroxy, C₁-C₈ alkyl, C₃-C₆ alkenyl, C₃-C₁₁ cycloalkyl, (C₃-C₁₁cycloalkyl)methyl, C₁-C₆ alkoxy,

benzyloxy, aryl, heteroaryl, heteroaryl(C₁-C₄ alkyl)-,

aryl(C₁-C₄ alkyl), adamantylmethyl, and

C₁-C₁₀ alkyl substituted with 0-2 R⁴,

alternatively, when R¹⁰ and R¹¹ are both substituents on the samenitrogen atom (as in —NR¹⁰R¹¹) they may be taken together with thenitrogen atom to which they are attached to form a heterocycle selectedfrom:

3-azabicyclononyl, 1,2,3,4-tetrahydro-1-quinolinyl,1,2,3,4-tetrahydro-2-isoquinolinyl, 1-piperidinyl, 1-morpholinyl,1-pyrrolidinyl, thiamorpholinyl, thiazolidinyl, and 1-piperazinyl;

said heterocycle being substituted with 0-3 groups selected from: C₁-C₆alkyl, aryl, heteroaryl, aryl(C₁-C₄ alkyl)-, (C₁-C₆ alkyl)carbonyl,(C₃-C₇ cycloalkyl)carbonyl, (C₁-C₆ alkoxy)carbonyl, aryl(C₁-C₄alkoxy)carbonyl, C₁-C₆ alkylsulfonyl, and arylsulfonyl;

R¹² is selected from:

H, C₁-C₆ alkyl, triphenylmethyl, methoxymethyl,methoxyphenyldiphenylmethyl,

trimethylsilylethoxymethyl, (C₁-C₆ alkyl)carbonyl,

(C₁-C₆ alkoxy)carbonyl, (C₁-C₆ alkyl)aminocarbonyl,

C₃-C₆ alkenyl, C₃-C₇ cycloalkyl, C₃-C₇ cycloalkyl(C₁-C₄ alkyl)-, aryl,heteroaryl(C₁-C₆ alkyl)carbonyl,

heteroarylcarbonyl, aryl(C₁-C₆ alkyl)-,

(C₁-C₆ alkyl)carbonyl, arylcarbonyl, C₁-C₆

alkylsulfonyl, arylsulfonyl, aryl(C₁-C₆ alkyl)sulfonyl,

heteroarylsulfonyl, heteroaryl(C₁-C₆ alkyl)sulfonyl,

aryloxycarbonyl, and aryl(C₁-C₆ alkoxy)carbonyl,

wherein said aryl groups are substituted with 0-2 substituents selectedfrom the group consisting of C₁-C₄ alkyl, C₁-C₄ alkoxy, halo, CF₃, andnitro;

R¹⁴ is selected from H, C₁-C₄ alkyl, and phenyl(C₁-C₄ alkyl);

R¹⁶ is selected from:

—C(═O)OR^(18a), —C(═O)R^(18b), —C(═O)N(R^(18b))₂, —C(═O)NHSO₂R^(18a),

—C(═O)NHC(═O)R^(18b), —C(═O)NHC(═O)OR^(18a),

—C(═O)NHSO₂NHR^(18b), —SO₂R^(18a), —SO₂N(R^(18b))₂, and

—SO₂NHC(═O)OR^(18b);

R¹⁷ is selected from:

H, C₁-C₆ alkyl, C₃-C₇ cycloalkyl, C₃-C₇ cycloalkyl(C₁-C₄ alkyl)-, aryl,aryl(C₁-C₆ alkyl)-, and heteroaryl(C₁-C₆ alkyl);

R^(18a) is selected from:

C₇-C₈ alkyl, C₃-C₁₁ cycloalkyl,

aryl(C₁-C₆ alkyl)-, said aryl substituted with 0-4 R¹⁹,

heteroaryl(C₁-C₆ alkyl)-, said heteroaryl substituted with 0-4 R¹⁹,

(C₁-C₆ alkyl)heteroaryl, said heteroaryl substituted with 0-4 R¹⁹,

heteroaryl substituted with 0-4 R¹⁹,

phenyl substituted with 3-4 R¹⁹, and

naphthyl substituted with 0-4 R¹⁹;

R^(18b) is H or R^(18a);

R¹⁹ is selected from:

H, halogen, CF₃, CO₂H, CN, N₂, —NR¹¹R¹², OCF₃,

C₁-C₈ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl,

C₃-C₁₁ cycloalkyl, C₃-C₇ cycloalkyl(C₁-C₄ alkyl)-,

aryl(C₁-C₆ alkyl)-, C₁-C₆ alkoxy, C₁-C₄ alkoxycarbonyl,

aryl, aryl-O—, aryl-SO₂—, heteroaryl, and

heteroaryl-SO₂—, wherein said aryl and heteroaryl groups are substitutedwith 0-4 groups selected from hydrogen, halogen, CF₃, C₁-C₃ alkyl, andC₁-C₃ alkoxy;

R²⁰ is selected from:

hydroxy, C₁-C₁₀ alkyloxy, C₃-C₁₁ cycloalkyloxy,

aryloxy, aryl(C₁-C₄ alkyl)oxy,

C₂-C₁₀ alkylcarbonyloxy(C₁-C₂ alkyl)oxy-,

C₂-C₁₀ alkoxycarbonyloxy (C₁-C₂ alkyl)oxy-,

C₂-C₁₀ alkoxycarbonyl (C₁-C₂ alkyl)oxy-,

C₃-C₁₀ cycloalkylcarbonyloxy(C₁-C₂ alkyl)oxy-,

C₃-C₁₀ cycloalkoxycarbonyloxy(C₁-C₂ alkyl)oxy-,

C₃-C₁₀ cycloalkoxycarbonyl (C₁-C₂ alkyl)oxy-,

aryloxycarbonyl(C₁-C₂ alkyl)oxy-,

aryloxycarbonyloxy(C₁-C₂ alkyl)oxy-,

arylcarbonyloxy(C₁-C₂ alkyl)oxy-,

C₁-C₅ alkoxy(C₁-C₅ alkyl)carbonyloxy(C₁-C₂ alkyl)oxy-,

(5-(C₁-C₅ alkyl)-1,3-dioxa-cyclopenten-2-one-yl)methyloxy,

(5-aryl-1,3-dioxa-cyclopenten-2-one-yl)methyloxy, and

(R¹⁰)(R¹¹)N—(C₁-C₁₀ alkoxy)-;

R²¹ is selected from:

C₁-C₈ alkyl, C₂-C₆ alkenyl, C₃-C₁₁ cycloalkyl, (C₃-C₁₁cycloalkyl)methyl, aryl, aryl(C₁-C₄ alkyl)-, and C₁-C₁₀ alkylsubstituted with 0-2 R⁷;

Y is selected from:

—COR²⁰, —SO₃H, —PO₃H, —CONHNHSO₂CF₃, —CONHSO₂R^(18a),

—CONHSO₂NHR^(18b), —NHCOCF₃, —NHCONHSO₂R^(18a), —NHSO₂R^(18a),

—OPO₃H₂, —OSO₃H, —PO₃H₂, —SO₃H,

—SO₂NHCOR^(18a), —SO₂NHCO₂R^(18a),

m is 0-2;

n is 0-4;

p is 0-2;

with the following provisos:

(1) n and m are chosen such that the number of atoms connecting R¹ and Yis in the range of 8-14;

(2) in W, the alkylene group is substituted with at least one R⁸ or R⁹which is not H;

(3) in the definition of W, when there is only one non-hydrogensubstituent on the alkylene group, such substituent may not be anunsubstituted pyridyl radical.

[1b] A preferred embodiment of the present invention are compounds ofFormula III:

including stereoisomeric forms thereof, or mixtures of stereoisomericforms thereof, or pharmaceutically acceptable salt or prodrug formsthereof wherein:

R¹ is selected from:

U is selected from —(CH₂)_(n)—, (CH₂)_(n)O(CH₂)_(m)—, —NH(CH₂)_(n)—,—(CH₂)_(n)C(═O)(CH₂)_(m)—, —N(R¹⁰)C(═O)—, and —NHC(═O)(CH₂)_(n)—;

R² and R³ are independently selected from:

H, C₁-C₄ alkoxy, NR¹¹R¹², halogen, NO₂, CN, CF₃, C₁-C₆ alkyl, C₃-C₆alkenyl, C₃-C₇ cycloalkyl,

C₃-C₇ cycloalkyl(C₁-C₄ alkyl), aryl(C₁-C₆ alkyl)-,

(C₁-C₆ alkyl)carbonyl, (C₁-C₆ alkoxy)carbonyl,

arylcarbonyl, and aryl substituted with 0-4 R⁷,

alternatively, when R² and R³ are substituents on adjacent atoms, theycan be taken together with the carbon atoms to which they are attachedto form a 5-7 membered carbocyclic or 5-7 membered heterocyclic aromaticor nonaromatic ring system, said carbocyclic or heterocyclic ring beingsubstituted with 0-2 groups selected from C₁-C₄ alkyl, C₁-C₄ alkoxy,halo, cyano, amino, CF₃ and NO₂;

R⁴ is selected from:

H, C₁-C₁₀ alkyl, (C₁-C₁₀ alkyl)carbonyl, aryl,

aryl(C₁-C₄ alkyl)-, C₃-C₁₁ cycloalkyl, and

C₃-C₁₁ cycloalkyl(C₁-C₄ alkyl)-;

R⁸ is selected from:

H, CO₂R^(18b), C(═O)R^(18b), CONR¹⁷R^(18b),

C₁-C₁ alkyl substituted with 0-1 R⁶,

C₅-C₁₀ alkenyl substituted with 0-1 R⁶,

C₅-C₁₀ alkynyl substituted with 0-1 R⁶,

C₃-C₈ cycloalkyl substituted with 0-1 R⁶,

C₅-C₆ cycloalkenyl substituted with 0-1 R⁶,

C₁-C₁₀ alkylcarbonyl,

C₃-C₁₀ cycloalkyl(C₁-C₄ alkyl)-,

phenyl substituted with 1-3 R⁶,

naphthyl substituted with 0-3 R⁶,

a 5-10 membered heterocyclic ring containing 1-3 N, O, or S heteroatoms,wherein said heterocyclic ring may be saturated, partially saturated, orfully unsaturated, said heterocyclic ring being substituted with 0-2 R⁷;

R⁹ is selected from:

H, hydroxy, C₅-C₁₀ alkoxy, nitro, N(R¹⁰)R¹¹, N(R¹⁶)R¹⁷, aryl(C₀-C₆alkyl)carbonyl, aryl(C₃-C₆ alkyl), heteroaryl(C₁-C₆ alkyl),CONR^(18a)R²⁰), SO₂R^(18a), SO₂NR^(18a)R²⁰),

C₁-C₁₀ alkyl substituted with 0-1 R⁶,

C₅-C₁₀ alkenyl substituted with 0-1 R⁶,

C₅-C₁₀ alkynyl substituted with 0-1 R⁶,

C₃-C₈ cycloalkyl substituted with 0-1 R⁶,

C₅-C₆ cycloalkenyl substituted with 0-1 R⁶,

C₁-C₁₀ alkylcarbonyl, C₃-C₁₀ cycloalkyl(C₁-C₄ alkyl),

phenyl substituted with 1-3 R⁶,

naphthyl substituted with 0-3 R⁶, and

a 5-10 membered heterocyclic ring containing 1-3 N, O, or S heteroatoms,wherein said heterocyclic ring may be saturated, partially saturated, orfully unsaturated, said heterocyclic ring being substituted with 0-2 R⁷,

providing that any of the above alkyl, cycloalkyl, aryl or heteroarylgroups may be unsubstituted or substituted independently with 1-2 R⁷;

R⁶ is selected from:

H, C₁-C₁₀ alkyl, hydroxy, C₁-C₁₀ alkoxy, nitro, C₁-C₁₀ alkylcarbonyl,—N(R¹¹)R¹², cyano, halo, CF₃, CHO, CO₂R^(18b), C(═O)R^(18b),CONR¹⁷R^(18b), OC(═O)R¹⁰, OR¹⁰, OC(═O)NR¹⁰R¹¹, NR¹⁰C(═O)R¹⁰,NR¹⁰C(═O)OR²¹, NR¹⁰C(═O)NR¹⁰R¹¹, NR¹⁰SO₂NR¹⁰R¹¹, NR¹⁰SO₂R²¹,S(O)_(p)R¹¹, SO₂NR¹⁰R¹¹,

aryl substituted with 0-3 groups selected from halogen, C₁-C₆ alkoxy,C₁-C₆ alkyl, CF₃, S(O)_(m)Me, and —NMe₂,

aryl(C₁-C₄ alkyl)-, said aryl being substituted with 0-3 groups selectedfrom halogen, C₁-C₆ alkoxy, C₁-C₆ alkyl, CF₃, S(O)_(p)Me, and —NMe₂, and

a 5-10 membered heterocyclic ring containing 1-3 N, O, or S heteroatoms,wherein said heterocyclic ring may be saturated, partially saturated, orfully unsaturated, said heterocyclic ring being substituted with 0-2 R⁷;

R⁷ is selected from:

H, hydroxy, C₁-C₄ alkyl, C₁-C₄ alkoxy, aryl, aryl(C₁-C₄ alkyl)-, (C₁-C₄alkyl)carbonyl, CO₂R^(18a), SO₂R¹¹,

SO₂NR¹⁰R¹¹, OR¹⁰, and N(R¹¹)R¹²;

R¹⁰ is selected from:

H, C₃-C₆ alkenyl, C₃-C₁₁ cycloalkyl, aryl,

(C₃-C₁₁ cycloalkyl)methyl, aryl(C₁-C₄ alkyl), and C₁-C₁₀ alkylsubstituted with 0-2 R⁶;

R¹¹ is selected from:

H, hydroxy, C₁-C₈ alkyl, C₃-C₆ alkenyl, C₃-C₁₁ cycloalkyl, (C₃-C₁₁cycloalkyl)methyl, C₁-C₆ alkoxy, benzyloxy, aryl, heteroaryl,heteroaryl(C₁-C₄ alkyl)-, aryl(C₁-C₄ alkyl), adamantylmethyl, and C₁-C₁₀alkyl substituted with 0-2 R⁴,

alternatively, when R¹⁰ and R¹¹ are both substituents on the samenitrogen atom (as in —NR¹⁰OR¹¹) they may be taken together with thenitrogen atom to which they are attached to form a heterocycle selectedfrom:

3-azabicyclononyl, 1,2,3,4-tetrahydro-1-quinolinyl,1,2,3,4-tetrahydro-2-isoquinolinyl, 1-piperidinyl, 1-morpholinyl,1-pyrrolidinyl, thiamorpholinyl, thiazolidinyl, and 1-piperazinyl;

said heterocycle being substituted with 0-3 groups selected from: C₁-C₆alkyl, aryl, heteroaryl, aryl(C₁-C₄ alkyl)-, (C₁-C₆ alkyl)carbonyl,(C₃-C₇ cycloalkyl)carbonyl, (C₁-C₆ alkoxy)carbonyl, aryl(C₁-C₄alkoxy)carbonyl, C₁-C₆ alkylsulfonyl, and arylsulfonyl;

R¹² is selected from:

H, C₁-C₆ alkyl, triphenylmethyl, methoxymethyl,methoxyphenyldiphenylmethyl,

trimethylsilylethoxymethyl, (C₁-C₆ alkyl)carbonyl,

(C₁-C₆ alkoxy)carbonyl, (C₁-C₆ alkyl)aminocarbonyl,

C₃-C₆ alkenyl, C₃-C₇ cycloalkyl, C₃-C₇ cycloalkyl(C₁-C₄ alkyl)-, aryl,heteroaryl(C₁-C₆ alkyl)carbonyl,

heteroarylcarbonyl, aryl(C₁-C₆ alkyl)-,

(C₁-C₆ alkyl)carbonyl, arylcarbonyl, C₁-C₆ alkylsulfonyl, arylsulfonyl,aryl(C₁-C₆ alkyl)sulfonyl,

heteroarylsulfonyl, heteroaryl(C₁-C₆ alkyl)sulfonyl,

aryloxycarbonyl, and aryl(C₁-C₆ alkoxy)carbonyl,

wherein said aryl groups are substituted with 0-2 substituents selectedfrom the group consisting of C₁-C₄ alkyl, C₁-C₄ alkoxy, halo, CF₃, andnitro;

R¹⁴ is selected from H, C₁-C₄ alkyl, and phenyl(C₁-C₄ alkyl);

R¹⁶ is selected from —C(═O)OR^(18a), —C(═O)R^(18b), —C(═O)N(R^(18b))₂,—SO₂R^(18a), and —SO₂N(R^(18b))₂;

R¹⁷ is selected from:

H, C₁-C₆ alkyl, C₃-C₇ cycloalkyl, C₃-C₇ cycloalkyl(C₁-C₄ alkyl)-, aryl,aryl(C₁-C₆ alkyl)-, and heteroaryl(C₁-C₆ alkyl);

R^(18a) is selected from:

C₇-C₈ alkyl, C₃-C₁₁ cycloalkyl,

aryl(C₁-C₆ alkyl)-, said aryl substituted with 0-4 R¹⁹,

heteroaryl(C₁-C₆ alkyl)-, said heteroaryl substituted with 0-4 R¹⁹,

(C₁-C₆ alkyl)heteroaryl, said heteroaryl substituted with 0-4 R¹⁹,

heteroaryl substituted with 0-4 R¹⁹,

phenyl substituted with 3-4 R¹⁹, and

naphthyl substituted with 0-4 R¹⁹;

R^(18b) is H or R^(18a);

R¹⁹ is selected from:

H, halogen, CF₃, CO₂H, CN, NO₂, —NR¹¹R¹², OCF₃,

C₁-C₈ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl,

C₃-C₁₁ cycloalkyl, C₃-C₇ cycloalkyl (C₁-C₄ alkyl)-,

aryl(C₁-C₆ alkyl)-, C₁-C₆ alkoxy, C₁-C₄ alkoxycarbonyl,

aryl, aryl-O—, aryl-SO₂—, heteroaryl, and

heteroaryl-SO₂—, wherein said aryl and heteroaryl groups are substitutedwith 0-4 groups selected from hydrogen, halogen, CF₃, C₁-C₃ alkyl, andC₁-C₃ alkoxy;

R²⁰ is selected from:

hydroxy, C₁-C₁₀ alkyloxy, C₃-C₁₁ cycloalkyloxy,

aryloxy, aryl(C₁-C₄ alkyl)oxy,

C₂-C₁₀ alkylcarbonyloxy(C₁-C₂ alkyl)oxy-,

C₂-C₁₀ alkoxycarbonyloxy(C₁-C₂ alkyl)oxy-,

C₂-C₁₀ alkoxycarbonyl(C₁-C₂ alkyl)oxy-,

C₃-C₁₀ cycloalkylcarbonyloxy(C₁-C₂ alkyl)oxy-,

C₃-C₁₀ cycloalkoxycarbonyloxy(C₁-C₂ alkyl)oxy-,

C₃-C₁₀ cycloalkoxycarbonyl(C₁-C₂ alkyl)oxy-,

aryloxycarbonyl(C₁-C₂ alkyl)oxy-,

aryloxycarbonyloxy(C₁-C₂ alkyl)oxy-,

arylcarbonyloxy(C₁-C₂ alkyl)oxy-,

C₁-C₅ alkoxy(C₁-C₅ alkyl)carbonyloxy(C₁-C₂ alkyl)oxy-,

(5-(C₁-C₅ alkyl)-1,3-dioxa-cyclopenten-2-one-yl)methyloxy,

(5-aryl-1,3-dioxa-cyclopenten-2-one-yl)methyloxy, and

(R¹⁰)(R¹¹)N—(C₁-C₁₀ alkoxy)-;

R²¹ is selected from:

C₁-C₈ alkyl, C₂-C₆ alkenyl, C₃-C₁₁ cycloalkyl, (C₃-C₁₁cycloalkyl)methyl, aryl, aryl(C₁-C₄ alkyl)-, and C₁-C₁₀ alkylsubstituted with 0-2 R⁷;

m is 0-2;

n is 0-3; and

p is 0-2;

with the following provisos:

(1) n and m are chosen such that the number of atoms connecting R¹ and—COR²⁰ in Formula (III) is in the range of 8-14,

(2) if R⁸ is H, then R⁹ may not be an unsubstituted pyridyl radical,

(3) if R⁹ is H, then R⁸ may not be an unsubstituted pyridyl radical.

[1c] A more preferred embodiment of the present invention are compoundsof Formula III:

including stereoisomeric forms thereof, or mixtures of stereoisomericforms thereof, or pharmaceutically acceptable salt or prodrug formsthereof wherein:

R¹ is selected from:

[1d] An even more preferred embodiment of the present invention arecompounds of Formula III:

including stereoisomeric forms thereof, or mixtures of stereoisomericforms thereof, or pharmaceutically acceptable salt or prodrug formsthereof wherein:

R¹ is selected from:

U is selected from —(CH₂)_(n)—, —NH(CH₂)_(n)—, —N(R¹⁰)C(═O)—, and—NHC(═O)(CH₂)_(n)—;

R⁴ is selected from:

H, C₁-C₄ alkyl, (C₁-C₄ alkyl)carbonyl, aryl,

aryl(C₁-C₄ alkyl)-, C₃-C₆ cycloalkyl, and

C₃-C₆ cycloalkyl(C₁-C₄ alkyl)-;

R⁶ is H;

R⁷ is selected from:

H, hydroxy, C₁-C₄ alkyl, C₁-C₄ alkoxy, aryl, aryl(C_(l)-C₄ alkyl)-,(C₁-C₄ alkyl)carbonyl, CO₂R^(18a), SO₂R¹¹, SO₂NR¹⁰R¹¹, OR¹⁰, andN(R¹¹)R¹²;

R⁸ is H;

R⁹ is selected from:

H, hydroxy, C₅-C₁₀ alkoxy, nitro, N(R¹⁰)R¹¹, N(R¹⁶)R¹⁷, aryl(C₀-C₆alkyl)carbonyl, aryl(C₃-C₆ alkyl), heteroaryl(C₁-C₆ alkyl),CONR^(18a)R²⁰, SO₂R^(18a), SO₂NR^(18a)R²⁰,

providing that any of the above alkyl, cycloalkyl, aryl or heteroarylgroups may be unsubstituted or substituted independently with 1-2 R⁷;

R¹⁰ is selected from:

H, C₃-C₆ alkenyl, C₃-C₆ cycloalkyl, aryl, (C₃-C₆ cycloalkyl)methyl,aryl(C₁-C₄ alkyl), and C₁-C₄ alkyl;

R¹¹ is selected from:

H, hydroxy, C₁-C₄ alkyl, C₃-C₆ alkenyl, C₃-C₆ cycloalkyl, (C₃-C₆cycloalkyl)methyl, C₁-C₆ alkoxy, benzyloxy, aryl, heteroaryl,heteroaryl(C₁-C₄ alkyl)-, aryl(C₁-C₄ alkyl), adamantylmethyl, and C₁-C₄alkyl substituted with 0-2 R⁴,

R¹² is selected from:

H, C₁-C₄ alkyl, (C₁-C₄ alkyl)carbonyl, (C₁-C₄ alkoxy)carbonyl,phenyl(C₁-C₄ alkyl)-, phenylsulfonyl,

phenyloxycarbonyl, and phenyl(C₁-C₄ alkoxy)carbonyl,

wherein said phenyl groups are substituted with 0-2 substituentsselected from the group consisting of C₁-C₄ alkyl, C₁-C₄ alkoxy, halo,CF₃, and nitro;

R¹⁴ is selected from H, methyl, ethyl, benzyl and phenylethyl;

R¹⁶ is selected from —C(═O)OR^(18a), —C(═O)R^(18b), —C(═O)N(R^(18b))₂,—SO₂R^(18a), and —SO₂N(R^(18b))₂;

R¹⁷ is selected from:

H, C₁-C₆ alkyl, C₃-C₇ cycloalkyl, C₃-C₇ cycloalkyl(C₁-C₄ alkyl)-, aryl,aryl(C₁-C₆ alkyl)-, and heteroaryl(C₁-C₆ alkyl);

R^(18a) is selected from:

C₇-C₈ alkyl, C₃-C₁₁ cycloalkyl,

aryl(C₁-C₆ alkyl)-, said aryl substituted with 0-4 R¹⁹,

heteroaryl(C₁-C₆ alkyl)-, said heteroaryl substituted with 0-4 R¹⁹,

(C₁-C₆ alkyl)heteroaryl, said heteroaryl substituted with 0-4 R¹⁹,

heteroaryl substituted with 0-4 R¹⁹,

phenyl substituted with 3-4 R¹⁹, and

naphthyl substituted with 0-4 R¹⁹;

R^(18b) is H or R^(18a);

R¹⁹ is selected from:

H, halogen, CF₃, CO₂H, CN, NO₂, —NR¹¹R¹², OCF₃,

C₁-C₈ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl,

C₃-C₁₁ cycloalkyl, C₃-C₇ cycloalkyl(C₁-C₄ alkyl)-,

aryl(C₁-C₆ alkyl)-, C₁-C₆ alkoxy, C₁-C₄ alkoxycarbonyl,

aryl, aryl-O—, aryl-SO₂—, heteroaryl, and

heteroaryl-SO₂—, wherein said aryl and heteroaryl groups are substitutedwith 0-4 groups selected from hydrogen, halogen, CF₃, C₁-C₃ alkyl, andC₁-C₃ alkoxy;

R²⁰ is selected from:

hydroxy C₁-C₁₀ alkyloxy, C₃-C₁₁ cycloalkyloxy,

aryloxy, aryl(C₁-C₄ alkyl)oxy,

C₂-C₁₀ alkylcarbonyloxy(C₁-C₂ alkyl)oxy-,

C₂-C₁₀ alkoxycarbonyloxy(C₁-C₂ alkyl)oxy-,

C₂-C₁₀ alkoxycarbonyl(C₁-C₂ alkyl)oxy-,

C₃-C₁₀ cycloalkylcarbonyloxy(C₁-C₂ alkyl)oxy- ,

C₃-C₁₀ cycloalkoxycarbonyloxy(C₁-C₂ alkyl)oxy-,

C₃-C₁₀ cycloalkoxycarbonyl(C₁-C₂ alkyl)oxy-,

aryloxycarbonyl (C₁-C₂ alkyl)oxy-,

aryloxycarbonyloxy(C₁-C₂ alkyl)oxy-,

arylcarbonyloxy(C₁-C₂ alkyl)oxy-,

C₁-C₅ alkoxy(C₁-C₅ alkyl)carbonyloxy(C₁-C₂ alkyl)oxy-,

(5(C₁-C₅ alkyl)-1,3-dioxa-cyclopenten-2-one-yl)methyloxy,

(5-aryl-1,3-dioxa-cyclopenten-2-one-yl)methyloxy, and

(R¹⁰)(R¹¹)N—(C₁-C₁₀ alkoxy)-;

R²¹ is selected from:

C₁-C₈ alkyl, C₂-C₆ alkenyl, C₃-C₁₁ cycloalkyl, (C₃-C₁₁cycloalkyl)methyl, aryl, aryl(C₁-C₄ alkyl)-, and C₁-C₁₀ alkylsubstituted with 0-2 R⁷;

m is 0-2;

n is 0-3; and

p is 0-2;

with the following provisos:

(1) n and m are chosen such that the number of atoms connecting R¹ and—COR²⁰ in Formula (III) is in the range of 8-14,

(2) if R⁸ is H, then R⁹ may not be an unsubstituted pyridyl radical,

(3) if R⁹ is H, then may not be an unsubstituted pyridyl radical.

[1e] Specifically preferred compounds of Formula III includingenantiomeric or diastereomeric forms thereof, or mixtures ofenantiomeric or diastereomeric forms thereof, or pharmaceuticallyacceptable salt or prodrug forms thereof selected from the groupconsisting of:

3-[7-[(imidazol-2-ylamino)methyl]-1-methylquinoline-4-one-3-ylcarbonylamino]-2-(3,5-dimethylisoxazol-4-ylsulfonylamino)propionicacid,

3-[7-[(imidazol-2-ylamino)methyl]-1-methylquinoline-4-one-3-ylcarbonylamino]-2-((2,4,6-trimethylphenyl)sulfonylamino)propionicacid,

3-[7-[(pyridin-2-ylamino)methyl]-1-methylquinoline-4-one-3-ylcarbonylamino]-2-((2,4,6-trimethylphenyl)sulfonylamino)propionicacid,

3-[7-[(imidazol-2-ylamino)methyl]-1-methylquinoline-4-one-3-ylcarbonylamino]-2-((4-phenylbenzene)sulfonylamino)propionicacid,

3-[7-[(benzimidazol-2-ylamino)methyl]-1-methylquinoline-4-one-3-ylcarbonylamino]-2-((2,4,6-trimethylphenyl)sulfonylamino)propionicacid,

3-[7-[(4-methylimidazol-2-ylamino)methyl]-1-methylquinoline-4-one-3-ylcarbonylamino]-2-((2,4,6-trimethylphenyl)sulfonylamino)propionicacid,

3-[7-[(4,5-dimethylimidazol-2-ylamino)methyl]-1-methylquinoline-4-one-3-ylcarbonylamino]-2-((2,4,6-trimethylphenyl)sulfonylamino)propionicacid,

3-[7-[(4,5,6,7-tetrahydrobenzimidazol-2-ylamino)methyl]-1-methylquinoline-4-one-3-ylcarbonylamino]-2-((2,4,6-trimethylphenyl)sulfonylamino)propionicacid,

3-[7-(2-aminopyridin-6-yl)quinoline-4-one-3-ylcarbonylamino]-2-((2,4,6-trimethylphenyl)sulfonylamino)propionicacid,

3-[7-[(7-azabenzimidazol-2-yl)methyl]-1-methylquinoline-4-one-3-ylcarbonylamino]-2-((2,4,6-trimethylphenyl)sulfonylamino)propionicacid,

3-[7-[(benzimidazol-2-ylamino)methyl]-1-(2-phenylethyl)quinoline-4-one-3-ylcarbonylamino]-2-((2,4,6-trimethylphenyl)sulfonylamino)propionicacid,

3-[7-[(pyridin-2-ylamino)methyl]-1-(2-phenylethyl)quinoline-4-one-3-ylcarbonylamino]-2-((2,4,6-trimethylphenyl)sulfonylamino)propionicacid,

3-[7-[(imidazol-2-ylamino)methyl]-1-(2-phenylethyl)quinoline-4-one-3-ylcarbonylamino]-2-((2,4,6-trimethylphenyl)sulfonylamino)propionicacid,

3-[7-[(imidazol-2-ylamino)methyl]-(2-phenylethyl)quinoline-4-one-3-ylcarbonylamino]-2-((2,4,6-trimethylphenyl)sulfonylamino)propionicacid,

3-[7-[(pyridin-2-ylamino)methyl]-(2-phenylethyl)quinoline-4-one-3-ylcarbonylamino]-2-((2,4,6-trimethylphenyl)sulfonylamino)propionicacid,

3-[7-[(imidazol-2-ylamino)methyl]-1-(2-phenylethyl)quinoline-4-one-3-ylcarbon-ylamino]-2-((4-phenylbenzene)sulfonylamino)propionicacid,

3-[7-[(benzimidazol-2-ylamino)methyl]-1-(2-phenylethyl)quinoline-4-one-3-ylcarbonylamino]-2-((2,4,6-trimethylphenyl)sulfonylamino)propionicacid,

3-[7-[(4-methylimidazol-2-ylamino)methyl]-(2-phenylethyl)quinoline-4-one-3-ylcarbonylamino]-2-((2,4,6-trimethylphenyl)sulfonylamino)propionicacid,

3-[7-[(4,5-dimethylimidazol-2-ylamino)methyl]-(2-phenylethyl)quinoline-4-one-3-ylcarbonylamino]-2-((2,4,6-trimethylphenyl)sulfonylamino)propionicacid,

3-[7-[(4,5,6,7-tetrahydrobenzimidazol-2-ylamino)methyl]-1-(2-phenylethyl)quinoline-4-one-3-ylcarbonylamino]-2-((2,4,6-trimethylphenyl)sulfonylamino)propionicacid,

3-[7-(2-aminopyridin-6-yl)1-(2-phenylethyl)quinoline-4-one-3-ylcarbonylamino]-2-((2,4,6-trimethylphenyl)sulfonylamino)propionicacid,

3-[7-[(7-azabenzimidazol-2-yl)methyl]-1-(2-phenylethyl)quinoline-4-one-3-ylcarbonylamino]-2-((2,4,6-trimethylphenyl)sulfonylamino)propionicacid,

3-[7-[(imidazol-2-ylamino)methyl]-1-(2-phenylethyl)quinoline-4-one-3-ylcarbon-ylamino]-2-((2,2-dimethyl-4-phenylbenzene)sulfonylamino)propionicacid,

3-[7-[(imidazol-2-ylamino)methyl]-1-(2-phenylethyl)quinoline-4-one-3-ylcarbon-ylamino]-2-((2,2-dichloro-4-phenylbenzene)sulfonylamino)propionicacid.

[2a] In a second embodiment of the present invention are compounds ofFormula II:

including stereoisomeric forms thereof, or mixtures of stereoisomericforms thereof, or pharmaceutically acceptable salt or prodrug formsthereof wherein:

R¹ is selected from:

A is —CH₂— or —N(R¹²)—;

A¹ and B are independently —CH₂— or —N(R¹⁰)—;

D is —N(R¹²)— or —S—;

E—F is —C(R²)═C(R³)— or —C(R²)₂C(R³)₂—;

J is —C(R²)— or —N—;

K, L and M are independently —C(R²)— or —C(R³)—;

R² and R³ are independently selected from:

H, C₁-C₄ alkoxy, NR¹¹R¹², halogen, N₂, CN, CF₃, C₁-C₆ alkyl, C₃-C₆alkenyl, C₃-C₇ cycloalkyl,

C₃-C₇ cycloalkyl(C₁-C₄ alkyl), aryl(C₁-C₆ alkyl)-,

(C₁-C₆ alkyl)carbonyl, (C₁-C₆ alkoxy)carbonyl,

arylcarbonyl, and aryl substituted with 0-4 R⁷,

alternatively, when R² and R³ are substituents on adjacent atoms, theycan be taken together with the carbon atoms to which they are attachedto form a 5-7 membered carbocyclic or 5-7 membered heterocyclic aromaticor nonaromatic ring system, said carbocyclic or heterocyclic ring beingsubstituted with 0-2 groups selected from C₁-C₄ alkyl, C₁-C₄ alkoxy,halo, cyano, amino, CF₃ and NO₂;

R^(2a) is selected from:

H, C₁-C₁₀ alkyl, C₂-C₆ alkenyl, C₃-C₁₁ cycloalkyl,

C₃-C₇ cycloalkyl(C₁-C₄ alkyl), aryl, aryl(C₁-C₄ alkyl)-, (C₂-C₇alkyl)carbonyl, arylcarbonyl,

(C₂-C₁₀ alkoxy)carbonyl, C₃-C₇ cycloalkoxycarbonyl,

C₇-C₁₁ bicycloalkoxycarbonyl, aryloxycarbonyl,

aryl(C₁-C₁₀ alkoxy)carbonyl,

C₁-C₆ alkylcarbonyloxy(C₁-C₄ alkoxy)carbonyl,

arylcarbonyloxy(C₁-C₄ alkoxy)carbonyl, and

C₃-C₇ cycloalkylcarbonyloxy(C₁-C₄ alkoxy)carbonyl;

R⁴ is selected from:

H, C₁-C₆ alkyl, C₃-C₇ cycloalkyl, C₃-C₇ cycloalkyl (C₁-C₄ alkyl)-,(C₁-C₁₀ alkyl)carbonyl, aryl, heteroaryl,

aryl(C₁-C₆ alkyl)-, and heteroaryl(C₁-C₆ alkyl)-,

wherein said aryl or heteroaryl groups are substituted with 0-2substituents independently selected from the group consisting of C₁-C₄alkyl, C₁-C₄ alkoxy, F, Cl, Br, CF₃, and NO₂,

R⁶ is selected from:

H, C₁-C₁₀ alkyl, hydroxy, C₁-C₁₀ alkoxy, nitro, C₁-C₁₀ alkylcarbonyl,—N(R¹¹)R¹², cyano, halo, CF₃, CHO, CO₂R^(18b), C(═O)R^(18b),CONR¹⁷R^(18b), OC(═O)R¹⁰, OR¹⁰, OC(═O)NR¹⁰R¹¹, NR¹⁰C(═O)R¹⁰,NR¹⁰C(═O)OR²¹, NR¹⁰C(═O)NR¹⁰R¹¹, NR¹⁰SO₂NR¹⁰R¹¹, NR¹⁰SO₂R²¹,S(O)_(p)R¹¹, SO₂NR¹⁰R¹¹,

aryl substituted with 0-3 groups selected from halogen, C₁-C₆ alkoxy,C₁-C₆ alkyl, CF₃, S(O)_(m)Me, and —NMe₂,

aryl(C₁-C₄ alkyl)-, said aryl being substituted with 0-3 groups selectedfrom halogen, C₁-C₆ alkoxy, C₁-C₆ alkyl, CF₃, S(O)_(p)Me, and —NMe₂, and

a 5-10 membered heterocyclic ring containing 1-3 N, O, or S heteroatoms,wherein said heterocyclic ring may be saturated, partially saturated, orfully unsaturated, said heterocyclic ring being substituted with 0-2 R⁷;

R⁷ is selected from:

H, hydroxy, C₁-C₄ alkyl, C₁-C₄ alkoxy, aryl, aryl(C₁-C₄ alkyl)-, (C₁-C₄alkyl)carbonyl, CO₂R^(18a), S₂R¹¹,

SO₂NR¹⁰R¹¹, OR¹⁰, and N(R¹¹)R¹²;

U is selected from:

—(CH₂)_(n)—, —(CH₂)_(n)O(CH₂)_(m)—, —(CH₂)_(n)N(R¹²)(CH₂)_(m)—,

—NH(CH₂)_(n)—, —(CH₂)_(n)C(═O)(CH₂)_(m)—, —(CH₂)_(n)S(O)_(p)(CH₂)_(m)—,

—(CH₂)_(n)NNHNH(CH₂)_(m)—, —N(R¹⁰)C(═O)—, —NHC(═O)(CH₂)_(n)—,

—C(═O)N(R¹⁰)—, and —N(R¹⁰)S(O)_(p)—;

G is N or CR¹⁹;

W is —C(═O)—N(R¹⁰)—(C₁-C₃ alkylene)-, in which the alkylene group issubstituted by R⁸ and by R⁹:

R⁸ and R⁹ are independently selected from:

H, CO₂R^(18b), C(═O)R^(18b), CONR¹⁷R^(18b),

C₁-C₁₀ alkyl substituted with 0-1 R⁶,

C₂-C₁₀ alkenyl substituted with 0-1 R⁶,

C₂-C₁₀ alkynyl substituted with 0-1 R⁶,

C₃-C₈ cycloalkyl substituted with 0-1 R⁶,

C₅-C₆ cycloalkenyl substituted with 0-1 R⁶,

(C₁-C₁₀ alkyl)carbonyl,

C₃-C₁₀ cycloalkyl(C₁-C₄ alkyl)-,

phenyl substituted with 0-3 R⁶,

naphthyl substituted with 0-3 R⁶,

a 5-10 membered heterocyclic ring containing 1-3 N, O, or S heteroatoms,wherein said heterocyclic ring may be saturated, partially saturated, orfully unsaturated, said heterocyclic ring being substituted with 0-2 R⁷,

C₁-C₁₀ alkoxy substituted with 0-2 R⁷,

hydroxy, nitro, —N(R¹⁰)R¹¹, —N(R¹⁶)R¹⁷, aryl(C₀-C₆ alkyl)carbonyl,aryl(C₃-C₆ alkyl), heteroaryl(C₁-C₆ alkyl), CONR^(18a)R²⁰), SO₂R^(18a),and SO₂NR^(18a)R²⁰,

providing that any of the above alkyl, cycloalkyl, aryl or heteroarylgroups may be unsubstituted or substituted independently with 1-2 R⁷;

R¹⁰ is selected from:

H, CF₃, C₃-C₆ alkenyl, C₃-C₁₁ cycloalkyl, aryl,

(C₃-C₁₁ cycloalkyl)methyl, aryl(C₁-C₄ alkyl), and C₁-C₁₀ alkylsubstituted with 0-2 R⁶;

R¹¹ is selected from:

H, hydroxy, C₁-C₈ alkyl, C₃-C₆ alkenyl, C₃-C₁₁ cycloalkyl, (C₃-C₁₁cycloalkyl)methyl, C₁-C₆ alkoxy,

benzyloxy, aryl, heteroaryl, heteroaryl(C₁-C₄ alkyl)-,

aryl(C₁-C₄ alkyl), adamantylmethyl, and

C₁-C₁₀ alkyl substituted with 0-2 R⁴;

alternatively, when R¹⁰ and R¹¹ are both substituents on the samenitrogen atom (as in —NR¹⁰R¹¹) they may be taken together with thenitrogen atom to which they are attached to form a heterocycle selectedfrom:

3-azabicyclononyl, 1,2,3,4-tetrahydro-1-quinolinyl,1,2,3,4-tetrahydro-2-isoquinolinyl, 1-piperidinyl, 1-morpholinyl,1-pyrrolidinyl, thiamorpholinyl, thiazolidinyl, and 1-piperazinyl;

said heterocycle being substituted with 0-3 groups selected from: C₁-C₆alkyl, aryl, heteroaryl, aryl(C₁-C₄ alkyl)-, (C₁-C₆ alkyl)carbonyl,(C₃-C₇ cycloalkyl)carbonyl, (C₁-C₆ alkoxy)carbonyl, aryl(C₁-C₄alkoxy)carbonyl, C₁-C₆ alkylsulfonyl, and arylsulfonyl;

R¹² is selected from:

H, C₁-C₆ alkyl, triphenylmethyl, methoxymethyl,

methoxyphenyldiphenylmethyl,

trimethylsilylethoxymethyl, (C₁-C₆ alkyl)carbonyl,

(C₁-C₆ alkoxy)carbonyl, (C₁-C₆ alkyl)aminocarbonyl,

C₃-C₆ alkenyl, C₃-C₇ cycloalkyl, C₃-C₇ cycloalkyl(C₁-C₄ alkyl)-, aryl,heteroaryl(C₁-C₆ alkyl)carbonyl,

heteroarylcarbonyl, aryl(C₁-C₆ alkyl)-,

(C₁-C₆ alkyl)carbonyl, arylcarbonyl, C₁-C₆

alkylsulfonyl, arylsulfonyl, aryl(C₁-C₆ alkyl)sulfonyl,

heteroarylsulfonyl, heteroaryl(C₁-C₆ alkyl)sulfonyl,

aryloxycarbonyl, and aryl(C₁-C₆ alkoxy)carbonyl,

wherein said aryl groups are substituted with 0-2 substituents selectedfrom the group consisting of C₁-C₄ alkyl, C₁-C₄ alkoxy, halo, CF₃, andnitro;

R¹⁶ is selected from:

—C(═O)OR^(18a), —C(═O)R^(18b), —C(═O)N(R^(18b))₂, —C(═O)NHSO₂R^(18a),

—C(═O)NHC(═O)R^(18b), —C(═O)NHC(═O)OR^(18a),

—C(═O)NHS₂NHR^(18b), —SO₂R^(18a), —SO₂N(R^(18b))₂, and

—SO₂NHC(═O)OR^(18b);

R¹⁷ is selected from:

H, C₁-C₆ alkyl, C₃-C₇ cycloalkyl, C₃-C₇ cycloalkyl(C₁-C₄ alkyl)-, aryl,aryl(C₁-C₆ alkyl)-, and heteroaryl(C₁-C₆ alkyl);

R^(18a) is selected from:

C₁-C₈ alkyl, C₃-C₁₁ cycloalkyl,

aryl(C₁-C₆ alkyl)-, said aryl substituted with 0-4 R¹⁹,

heteroaryl(C₁-C₆ alkyl)-, said heteroaryl substituted with 0-4 R¹⁹,

(C₁-C₆ alkyl)heteroaryl, said heteroaryl substituted with 0-4 R¹⁹,

heteroaryl substituted with 0-4 R¹⁹

phenyl substituted with 0-4 R¹⁹, and

naphthyl substituted with 0-4 R¹⁹;

R^(18b)is H or R^(18a);

R¹⁹ is selected from:

H, halogen, CF₃, CO₂H, CN, N₂, —NR¹¹R¹², OCF₃,

C₁-C₈ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl,

C₃-C₁₁ cycloalkyl, C₃-C₇ cycloalkyl(C₁-C₄ alkyl)-,

aryl(C₁-C₆ alkyl)-, C₁-C₆ alkoxy, C₁-C₄ alkoxycarbonyl,

aryl, aryl-O—, aryl-SO₂—, heteroaryl, and

heteroaryl-SO₂—, wherein said aryl and heteroaryl groups are substitutedwith 0-4 groups selected from hydrogen, halogen, CF₃, C₁-C₃ alkyl, andC₁-C₃ alkoxy;

R²⁰ is selected from:

hydroxy, C₁-C₁₀ alkyloxy, C₃-C₁₁ cycloalkyloxy,

aryloxy, aryl(C₁-C₄ alkyl)oxy,

C₂-C₁₀ alkylcarbonyloxy(C₁-C₂ alkyl)oxy-,

C₂-C₁₀ alkoxycarbonyloxy(C₁-C₂ alkyl)oxy-,

C₂-C₁₀ alkoxycarbonyl(C₁-C₂ alkyl)oxy-,

C₃-C₁₀ cycloalkylcarbonyloxy(C₁-C₂ alkyl)oxy-,

C₃-C₁₀ cycloalkoxycarbonyloxy(C₁-C₂ alkyl)oxy-,

C₃-C₁₀ cycloalkoxycarbonyl(C₁-C₂ alkyl)oxy-,

aryloxycarbonyl(C₁-C₂ alkyl)oxy-,

aryloxycarbonyloxy(C₁-C₂ alkyl)oxy-,

arylcarbonyloxy(C₁-C₂ alkyl)oxy-,

C₁-C₅ alkoxy(C₁-C₅ alkyl)carbonyloxy(C₁-C₂ alkyl)oxy-,

(5-(C₁-C₅ alkyl)-1,3-dioxa-cyclopenten-2-one-yl)methyloxy,

(5-aryl-1,3-dioxa-cyclopenten-2-one-yl)methyloxy, and

(R¹⁰)(R¹¹)N—(C₁-C₁₀ alkoxy)—;

R²¹ is selected from:

C₁-C₈ alkyl, C₂-C₆ alkenyl, C₃-C₁₁ cycloalkyl, (C₃-C₁₁cycloalkyl)methyl, aryl, aryl(C₁-C₄ alkyl)-, and C₁-C₁₀ alkylsubstituted with 0-2 R⁷;

R²² is selected from:

—C(═O)—R^(18b), —C(═O)N(R^(18b))₂, —C(═O)NHSO₂R^(18a),

—C(═O)NHC(═O)R^(18b), —C(═O)NHC(═O)OR^(18a), and

—C(═O)NHSO₂NHR^(18b);

Y is selected from:

—COR²⁰, —SO₃H, —PO₃H, —CONHNHSO₂CF₃, —CONHSO₂R^(18a),

—CONHSO₂NHR^(18b), —NHCOCF₃, —NHCONHSO₂R^(18a), —NHS₂R^(18a),

—OPO₃H₂, —OSO₃H, —PO₃H₂, —SO₂NHCOR^(18a), —SO₂NHCO₂R^(18a),

m is 0-2;

n is 0-4;

p is 0-2;

r is 0-2;

with the following provisos:

(1) n and m are chosen such that the number of atoms connecting R¹ and Yis in the range of 8-14,

(2) when R¹⁰ is hydrogen, C₁-C₄ alkyl, or phenyl(C₁-C₄ alkyl) and allR¹⁹ groups are H, G is N,

(3) when G is CR¹⁹, at least one R¹⁹ group cannot be H.

[2b] Preferred compounds in the second embodiment are compounds ofFormula IV:

including stereoisomeric forms thereof, or mixtures of stereoisomericforms thereof, or pharmaceutically acceptable salt or prodrug formsthereof wherein:

R¹ is selected from:

R² and R³ are independently selected from:

H, C₁-C₄ alkoxy, NR¹¹R¹², halogen, NO₂, CN, CF₃, C₁-C₆ alkyl, C₃-C₆alkenyl, C₃-C₇ cycloalkyl,

C₃-C₇ cycloalkyl(C₁-C₄ alkyl), aryl(C₁-C₆ alkyl)-,

(C₁-C₆ alkyl)carbonyl, (C₁-C₆ alkoxy)carbonyl,

arylcarbonyl, and aryl substituted with 0-4 R⁷,

alternatively, when R² and R³ are substituents on adjacent atoms, theycan be taken together with the carbon atoms to which they are attachedto form a 5-7 membered carbocyclic or 5-7 membered heterocyclic aromaticor nonaromatic ring system, said carbocyclic or heterocyclic ring beingsubstituted with 0-2 groups selected from C₁-C₄ alkyl, C₁-C₄ alkoxy,halo, cyano, amino, CF₃ and NO₂;

R^(2a) is selected from:

H, C₁-C₁₀ alkyl, C₂-C₆ alkenyl, C₃-C₁₁ cycloalkyl,

C₃-C₇ cycloalkyl(C₁-C₄ alkyl), aryl, aryl(C₁-C₄ alkyl)-, (C₂-C₇alkyl)carbonyl, arylcarbonyl,

(C₂-C₁₀ alkoxy)carbonyl, C₃-C₇ cycloalkoxycarbonyl,

C₇-C₁₁ bicycloalkoxycarbonyl, aryloxycarbonyl, aryl(C₁-C₁₀alkoxy)carbonyl,

C₁-C₆ alkylcarbonyloxy(C₁-C₄ alkoxy)carbonyl,

arylcarbonyloxy(C₁-C₄ alkoxy)carbonyl, and

C₃-C₇ cycloalkylcarbonyloxy(C₁-C₄ alkoxy)carbonyl;

R⁴ is selected from:

H, C₁-C₆ alkyl, C₃-C₇ cycloalkyl, C₃ 14 C₇ cycloalkyl(C₁-C₄ alkyl)-,aryl, heteroaryl, aryl(C₁-C₆ alkyl)-, and

heteroaryl(C₁-C₆ alkyl)-, wherein said aryl or heteroaryl groups aresubstituted with 0-2 substituents independently selected from the groupconsisting of C₁-C₄ alkyl, C₁-C₄ alkoxy, F, Cl, Br, CF₃, and NO₂,

R⁶ is selected from:

H, C₁-C₁₀ alkyl, hydroxy, C₁-C₁₀ alkoxy, nitro, C₁-C₁₀ alkylcarbonyl,—N(R¹¹)R¹², cyano, halo, CF₃, CHO, CO₂R^(18b), C(═O)R^(18b),CONR¹⁷R^(18b), OC(═O)R¹⁰, OR¹⁰, OC(═O)NR¹⁰R¹¹, NR¹⁰C(═O)R¹⁰,NR¹⁰C(═O)OR²¹, NR¹⁰C(═O)NR¹⁰R¹¹, NR¹⁰SO₂NR¹⁰R¹¹, NR¹⁰SO₂R²¹,S(O)_(p)R¹¹, SO₂NR¹⁰R¹¹,

aryl substituted with 0-3 groups selected from halogen, C_(l)-C₆ alkoxy,C₁-C₆ alkyl, CF₃, S(O)_(m)Me, and —NMe₂,

aryl(C₁-C₄ alkyl)-, said aryl being substituted with 0-3 groups selectedfrom halogen, C₁-C₆ alkoxy, C₁-C₆ alkyl, CF₃, S(O)_(p)Me, and —NMe₂, and

a 5-10 membered heterocyclic ring containing 1-3 N, O, or S heteroatoms,wherein said heterocyclic ring may be saturated, partially saturated, orfully unsaturated, said heterocyclic ring being substituted with 0-2 R⁷;

R⁷ is selected from:

H, hydroxy, C₁-C₄ alkyl, C₁-C₄ alkoxy, aryl, aryl(C₁-C₄ alkyl)-, (C₁-C₄alkyl)carbonyl, CO₂R^(18a), SO₂R¹¹,

SO₂NR¹⁰R¹¹, OR¹⁰, and N(R¹¹)R¹²;

U is selected from:

—(CH₂)_(n)—, —(CH₂)_(n)O(CH₂)_(m)—, —NH(CH₂)_(n)—, —N(R¹⁰)C(═O)—,

—NHC(═O)(CH₂)_(n)— and —C(═O)N(R¹⁰)—;

G is N or CR¹⁹;

R⁸ is selected from:

H, CO₂R^(18b), C(═O)R^(18b), CONR¹⁷R^(18b),

C₁-C₁₀ alkyl substituted with 0-1 R⁶,

C₂-C₁₀ alkenyl substituted with 0-1 R⁶,

C₂-C₁₀ alkynyl substituted with 0-1 R⁶,

C₃-C₈ cycloalkyl substituted with 0-1 R⁶,

C₅-C₆ cycloalkenyl substituted with 0-1 R⁶,

(C₁-C₁₀ alkyl)carbonyl,

C₃-C₁₀ cycloalkyl(C₁-C₄ alkyl)-,

phenyl substituted with 0-3 R⁶,

naphthyl substituted with 0-3 R⁶,

a 5-10 membered heterocyclic ring containing 1-3 N, O, or S heteroatoms,wherein said heterocyclic ring may be saturated, partially saturated, orfully unsaturated, said heterocyclic ring being substituted with 0-2 R⁷;

R⁹ is selected from:

C₁-C₁₀ alkyl substituted with 0-1 R⁶,

C₁-C₁₀ alkoxy substituted with 0-2 R⁷,

H, nitro, N(R¹¹)R¹², OC(═O)R¹⁰, OR¹⁰, OC(═O)NR¹⁰OR¹¹, NR¹⁰C(═O)R¹⁰),NR¹⁰C(═O)OR²¹, NR¹⁰C(═O)NR¹⁰R¹¹, NR¹⁰SO₂NR¹⁰R¹¹, NR¹⁰SO₂R²¹, hydroxy,OR²², —N(R¹⁰)R¹¹, —N(R¹⁶)R¹⁷, aryl(C₀-C₆ alkyl)carbonyl, aryl(C₁-C₆alkyl), heteroaryl(C₁-C₆ alkyl), CONR^(18a)R²⁰, SO₂R^(18a), andSO₂NR^(18a)R²⁰,

providing that any of the above alkyl, cycloalkyl, aryl or heteroarylgroups may be unsubstituted or substituted independently with 1-2 R⁷;

R¹⁰ is selected from:

H, CF₃, C₃-C₆ alkenyl, C₃-C₁₁ cycloalkyl, aryl,

(C₃-C₁₁ cycloalkyl)methyl, aryl(C₁-C₄ alkyl), and C₁-C₁₀ alkylsubstituted with 0-2 R⁶;

R¹¹ is selected from:

H, hydroxy, C₁-C₈ alkyl, C₃-C₆ alkenyl, C₃-C₁₁ cycloalkyl, (C₃-C₁₁cycloalkyl)methyl, C₁-C₆ alkoxy,

benzyloxy, aryl, heteroaryl, heteroaryl(C₁-C₄ alkyl)-,

aryl(C₁-C₄ alkyl), adamantylmethyl, and

C₁-C₁₀ alkyl substituted with 0-2 R⁴;

R¹² is selected from:

H, C₁-C₆ alkyl, triphenylmethyl, methoxymethyl,

methoxyphenyldiphenylmethyl,

trimethylsilylethoxymethyl, (C₁-C₆ alkyl)carbonyl,

(C₁-C₆ alkoxy)carbonyl, (C₁-C₆ alkyl)aminocarbonyl,

C₃-C₆ alkenyl, C₃-C₇ cycloalkyl, C₃-C₇ cycloalkyl(C₁-C₄ alkyl)-, aryl,heteroaryl(C₁-C₆ alkyl)carbonyl,

heteroarylcarbonyl, aryl(C₁-C₆ alkyl)-,

(C₁-C₆ alkyl)carbonyl, arylcarbonyl, C₁-C₆ alkylsulfonyl, arylsulfonyl,aryl(C₁-C₆ alkyl)sulfonyl,

heteroarylsulfonyl, heteroaryl(C₁-C₆ alkyl)sulfonyl,

aryloxycarbonyl, and aryl(C₁-C₆ alkoxy)carbonyl,

wherein said aryl groups are substituted with 0-2 substituents selectedfrom the group consisting of C₁-C₄ alkyl, C₁-C₄ alkoxy, halo, CF₃, andnitro;

R¹⁶ is selected from:

—C(═O)OR^(18a), —C(═O)R^(18b), —C(═O)N(R^(18b))₂, —SO₂R^(18a), and

—SO₂N(R^(18b))₂;

R¹⁷ is selected from:

H, C₁-C₆ alkyl, C₃-C₇ cycloalkyl, C₃-C₇ cycloalkyl(C₁-C₄ alkyl)-, aryl,aryl(C₁-C₆ alkyl)-, and heteroaryl(C₁-C₆ alkyl);

R^(18a) is selected from:

C₁-C₈ alkyl, C₃-C₁₁ cycloalkyl,

aryl(C₁-C₆ alkyl)-, said aryl substituted with 0-4 R¹⁹,

heteroaryl(C₁-C₆ alkyl)-, said heteroaryl substituted with 0-4 R¹⁹,

(C₁-C₆ alkyl)heteroaryl, said heteroaryl substituted with 0-4 R¹⁹,

heteroaryl substituted with 0-4 R¹⁹,

phenyl substituted with 0-4 R¹⁹, and

naphthyl substituted with 0-4 R¹⁹;

R^(18b) is H or R^(18a);

R¹⁹ is selected from:

H, halogen, CF₃, CO₂H, CN, NO₂, —NR¹¹R¹², OCF₃,

C₁-C₈ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl,

C₃-C₁₁ cycloalkyl, C₃-C₇ cycloalkyl(C₁-C₄ alkyl)-,

aryl(C₁-C₆ alkyl)-, C₁-C₆ alkoxy, C₁-C₄ alkoxycarbonyl,

aryl, aryl-O—, aryl-SO₂—, heteroaryl, and

heteroaryl-SO₂—, wherein said aryl and heteroaryl groups are substitutedwith 0-4 groups selected from hydrogen, halogen, CF₃, C₁-C₃ alkyl, andC₁-C₃ alkoxy;

R²⁰ is selected from:

hydroxy, C₁-C₁₀ alkyloxy, C₃-C₁₁ cycloalkyloxy,

aryloxy, aryl(C₁-C₄ alkyl)oxy,

C₂-C₁₀ alkylcarbonyloxy(C₁-C₂ alkyl)oxy-,

C₂-C₁₀ alkoxycarbonyloxy(C₁-C₂ alkyl)oxy-,

C₂-C₁₀ alkoxycarbonyl(C₁-C₂ alkyl)oxy-,

C₃-C₁₀ cycloalkylcarbonyloxy(C₁-C₂ alkyl)oxy-,

C₃-C₁₀ cycloalkoxycarbonyloxy(C₁-C₂ alkyl)oxy-,

C₃-C₁₀ cycloalkoxycarbonyl(C₁-C₂ alkyl)oxy-,

aryloxycarbonyl(C₁-C₂ alkyl)oxy-,

aryloxycarbonyloxy(C₁-C₂ alkyl)oxy-,

arylcarbonyloxy(C₁-C₂ alkyl)oxy-,

C₁-C₅ alkoxy(C₁-C₅ alkyl)carbonyloxy(C₁-C₂ alkyl)oxy-,

(5-(C₁-C₅ alkyl)-1,3-dioxa-cyclopenten-2-one-yl)methyloxy,

(5-aryl-1,3-dioxa-cyclopenten-2-one-yl)methyloxy, and

(R¹⁰)(R¹¹)N—(C₁-C₁₀ alkoxy)-;

R²¹ is selected from:

C₁-C₈ alkyl, C₂-C₆ alkenyl, C₃-C₁₁ cycloalkyl, (C₃-C₁₁cycloalkyl)methyl, aryl, aryl(C₁-C₄ alkyl)-, and C₁-C₁₀ alkylsubstituted with 0-2 R⁷;

R²² is selected from:

—C(═O)—R^(18b), —C(═O)N(R^(18b))₂, —C(═O)NHSO₂R^(18a),

—C(═O)NHC(═O)R^(18b), —C(═O)NHC(═O)OR^(18a), and

—C (═O)NHSO₂NHR^(18b);

m is 0-2;

n is 0-4; and

p is 0-2;

with the following provisos:

(1) n and m are chosen such that the number of atoms connecting R¹ and—COR²⁰ in Formula (IV) is in the range of 8-14,

(2) when R¹⁰ is hydrogen, C₁-C₄ alkyl, or phenyl(C₁-C₄ alkyl) and allR¹⁹ groups are H, G is N,

(3) when G is CR¹⁹, at least one R¹⁹ group cannot be H.

[2c] More preferred compounds in the second embodiment are compounds ofFormula IV:

including stereoisomeric forms thereof, or mixtures of stereoisomericforms thereof, or pharmaceutically acceptable salt or prodrug formsthereof wherein:

R¹ is selected from:

R² and R³ are independently selected from:

H, C₁-C₄ alkoxy, NR¹¹R¹², halogen, NO₂, CN, CF₃, C₁-C₆ alkyl, C₃-C₆alkenyl, C₃-C₇ cycloalkyl,

C₃-C₇ cycloalkyl(C₁-C₄ alkyl), aryl(C₁-C₆ alkyl)-,

(C₁-C₆ alkyl)carbonyl, (C₁-C₆ alkoxy)carbonyl,

arylcarbonyl, and aryl substituted with 0-4 R⁷,

alternatively, when R² and R³ are substituents on adjacent atoms, theycan be taken together with the carbon atoms to which they are attachedto form a 5-7 membered carbocyclic or 5-7 membered heterocyclic aromaticor nonaromatic ring system, said carbocyclic or heterocyclic ring beingsubstituted with 0-2 groups selected from C₁-C₄ alkyl, C₁-C₄ alkoxy,halo, cyano, amino, CF₃ and NO₂;

R^(2a) is selected from:

H, C₁-C₁₀ alkyl, C₂-C₆ alkenyl, C₃-C₁₁ cycloalkyl,

C₃-C₇ cycloalkyl(C₁-C₄ alkyl), aryl, aryl(C₁-C₄ alkyl)-, (C₂-C₇alkyl)carbonyl, arylcarbonyl,

(C₂-C₁₀ alkoxy)carbonyl, C₃-C₇ cycloalkoxycarbonyl,

C₇-C₁₁ bicycloalkoxycarbonyl, aryloxycarbonyl,

aryl(C₁-C₁₀ alkoxy)carbonyl,

C₁-C₆ alkylcarbonyloxy(C₁-C₄ alkoxy)carbonyl,

arylcarbonyloxy(C₁-C₄ alkoxy)carbonyl, and

C₃-C₇ cycloalkylcarbonyloxy(C₁-C₄ alkoxy)carbonyl;

R⁴ is selected from:

H, C₁-C₄ alkyl, C₃-C₇ cycloalkyl, C₃-C₇ cycloalkyl(C₁-C₄ alkyl)-, aryl,heteroaryl, aryl(C₁-C₄ alkyl)-, and

heteroaryl(C₁-C₄ alkyl)-, wherein said aryl or heteroaryl groups aresubstituted with 0-2 substituents independently selected from the groupconsisting of C₁-C₄ alkyl, C₁-C₄ alkoxy, F, Cl, Br, CF₃, and NO₂,

R⁶ is selected from:

H, C₁-C₄ alkyl, hydroxy, C₁-C₄ alkoxy, nitro, C₁-C₄ alkylcarbonyl,—N(R¹¹)R¹², cyano, halo, CF₃, CHO, CO₂R^(18b), C(═O)R^(18b),CONR¹⁷R^(18b), OC(═O)R¹⁰, OR¹⁰, OC(═O)NR¹⁰R¹¹, NR¹⁰C(═O)R¹⁰,NR¹⁰C(═O)OR²¹, NR¹⁰C(═O) NR¹⁰R¹¹, NR¹⁰SO₂NR^(1o)R¹¹, NR¹⁰SO₂R²¹,S(O)_(p)R¹¹, SO₂NR¹⁰R¹¹,

aryl substituted with 0-3 groups selected from halogen, C₁-C₄ alkoxy,C₁-C₄ alkyl, CF₃, S(O)_(m)Me, and —NMe₂,

aryl(C₁-C₄ alkyl)-, said aryl being substituted with 0-3 groups selectedfrom halogen, C₁-C₄ alkoxy, C₁-C₄ alkyl, CF₃, S(O)_(p)Me, and —NMe₂, and

a 5-10 membered heterocyclic ring containing 1-3 N, O, or S heteroatoms,wherein said heterocyclic ring may be saturated, partially saturated, orfully unsaturated, said heterocyclic ring being substituted with 0-2 R⁷;

R⁷ is selected from:

H, hydroxy, C₁-C₄ alkyl, C₁-C₄ alkoxy, aryl, aryl(C₁-C₄ alkyl)-, (C₁-C₄alkyl)carbonyl, CO₂R^(18a), SO₂R¹¹,

SO₂NR¹⁰R¹¹, OR¹⁰, and N(R¹¹)R¹²;

U is selected from:

—(CH₂)_(n)—, —NH(CH₂)_(n)—, —N(R¹⁰)C(═O)—, and —NHC(═O)(CH₂)_(n);

G is N or CR¹⁹;

R⁸ is H;

R⁹ is selected from:

H, nitro, N(R¹¹)R¹², OC(═O)R¹⁰, OR¹⁰, OC(═O)NR¹⁰R¹¹, NR¹⁰C(═O)R¹⁰,NR¹⁰C(═O)OR²¹, NR¹⁰C(═O)NR¹⁰R¹¹, NR¹⁰SO₂NR¹⁰R¹¹, NR¹⁰SO₂R²¹, hydroxy,OR²², —N(R¹⁰)R¹¹, —N(R¹⁶)R¹⁷, aryl(C₀-C₄ alkyl)carbonyl, aryl(C₁-C₄alkyl), heteroaryl(C₁-C₄ alkyl), CONR^(18a)R²⁰, SO₂R^(18a), andSO₂NR^(18a)R²⁰,

providing that any of the above alkyl, cycloalkyl, aryl or heteroarylgroups may be unsubstituted or substituted independently with 1-2 R⁷;

R¹⁰ is selected from:

H, CF₃, C₃-C₆ alkenyl, C₃-C₆ cycloalkyl, aryl,

(C₃-C₆ cycloalkyl)methyl, aryl(C₁-C₄ alkyl), and C₁-C₄ alkyl substitutedwith 0-2 R⁶;

R¹¹ is selected from:

H, hydroxy, C₁-C₄ alkyl, C₃-C₆ alkenyl, C₃-C₆ cycloalkyl, (C₃-C₆cycloalkyl)methyl, C₁-C₄ alkoxy,

benzyloxy, aryl, heteroaryl, heteroaryl(C₁-C₄ alkyl)-,

aryl(C₁-C₄ alkyl), adamantylmethyl, and

C₁-C₄ alkyl substituted with 0-2 R⁴;

R¹² is selected from:

H, C₁-C₄ alkyl, (C₁-C₄ alkyl)carbonyl, (C₁-C₄ alkoxy)carbonyl,phenyl(C₁-C₄ alkyl)-, phenylsulfonyl,

phenyloxycarbonyl, and phenyl(C₁-C₄ alkoxy)carbonyl,

wherein said phenyl groups are substituted with 0-2 substituentsselected from the group consisting of C₁-C₄ alkyl, C₁-C₄ alkoxy, halo,CF₃, and nitro;

R¹⁶ is selected from:

—C(═O)OR^(18a), —C(═O)R^(18b), —C(═O)N(R^(18b))₂, —SO₂R^(18a), and

—SO₂N (R^(18b))₂;

R¹⁷ is selected from:

H, C₁-C₄ alkyl, C₃-C₆ cycloalkyl, C₃-C₆ cycloalkyl(C₁-C₄ alkyl)-, aryl,aryl(C₁-C₆ alkyl)-, and heteroaryl(C₁-C₆ alkyl);

R^(18a) is selected from:

C₁-C₄ alkyl, C₃-C₆ cycloalkyl, aryl(C₁-C₄ alkyl)-, said aryl substitutedwith 0-4 R¹⁹,

heteroaryl(C₁-C₄ alkyl)-, said heteroaryl substituted with 0-4 R¹⁹,

(C₁-C₄ alkyl)heteroaryl, said heteroaryl substituted with 0-4 R¹⁹,

heteroaryl substituted with 0-4 R¹⁹,

phenyl substituted with 0-4 R¹⁹, and

naphthyl substituted with 0-4 R¹⁹;

R^(18b) is H or R^(18a);

R¹⁹ is selected from:

H, halogen, CF₃, CO₂H, CN, NO₂, —NR¹¹R¹², OCF₃,

C₁-C₆ alkyl, C₂-C₄ alkenyl, C₂-C₆ alkynyl,

C₃-C₆ cycloalkyl, C₃-C₆ cycloalkyl(C₁-C₄ alkyl)-,

aryl(C₁-C₄ alkyl)-, C₁-C₆ alkoxy, C₁-C₄ alkoxycarbonyl,

aryl, aryl-O—, aryl-SO₂—, heteroaryl, and

heteroaryl-SO₂—, wherein said aryl and heteroaryl groups are substitutedwith 0-4 groups selected from hydrogen, halogen, CF₃, C₁-C₃ alkyl, andC₁-C₃ alkoxy;

R²⁰ is selected from:

hydroxy, C₁-C₆ alkyloxy, C₃-C₆ cycloalkyloxy, aryloxy,

aryl(C₁-C₄ alkyl)oxy,

C₂-C₁₀ alkylcarbonyloxy(C₁-C₂ alkyl)oxy-,

C₂-C₁₀ alkoxycarbonyloxy(C₁-C₂ alkyl)oxy-,

C₂-C₁₀ alkoxycarbonyl(C₁-C₂ alkyl)oxy-, C₃-C₁₀cycloalkylcarbonyloxy(C₁-C₂ alkyl)oxy-,

C₃-C₁₀ cycloalkoxycarbonyloxy(C₁-C₂ alkyl)oxy-,

C₃-C₁₀ cycloalkoxycarbonyl(C₁-C₂ alkyl)oxy-,

aryloxycarbonyl(C₁-C₂ alkyl)oxy-,

aryloxycarbonyloxy(C₁-C₂ alkyl)oxy-,

arylcarbonyloxy(C₁-C₂ alkyl)oxy-,

C₁-C₅ alkoxy(C₁-C₅ alkyl)carbonyloxy(C₁-C₂ alkyl)oxy-,

(5-(C₁-C₅ alkyl)-1,3-dioxa-cyclopenten-2-one-yl)methyloxy,

(5-aryl-1,3-dioxa-cyclopenten-2-one-yl)methyloxy, and

(R¹⁰)(R¹¹)N—(C₁-C₁₀ alkoxy)-;

R²¹ is selected from:

C₁-C₄ alkyl, C₂-C₆ alkenyl, C₃-C₆ cycloalkyl, (C₃-C₆ cycloalkyl)methyl,aryl, aryl(C₁-C₄ alkyl)-, and C₁-C₁₀ alkyl substituted with 0-2 R⁷;

R²² is selected from:

—C(═O)—R^(18b), —C(═O)N(R^(18b))₂, —C(═O)NHSO₂R^(18a),

—C(═O)NHC(═O)R^(18b), —C(═O)NHC(═O)OR^(18a), and

—C(═O)NHSO₂NHR^(18b);

m is 0-2;

n is 0-4; and

p is 0-2;

with the following provisos:

(1) n and m are chosen such that the number of atoms connecting R¹ and—COR²⁰ in Formula (IV) is in the range of 8-14,

(2) when R¹⁰ is hydrogen, C₁-C₄ alkyl, or phenyl(C₁-C₄ alkyl) and allR¹⁹ groups are H, G is N,

(3) when G is CR¹⁹, at least one R¹⁹ group cannot be H.

[2d] Specifically preferred compounds of the above invention arecompounds of Formula IV including enantiomeric or diastereomeric formsthereof, or mixtures of enantiomeric or diastereomeric forms thereof, orpharmaceutically acceptable salt or prodrug forms thereof selected fromthe group consisting of:

3-[7-[(imidazolin-2-ylamino)methyl]-1-methyl-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-(3,5-dimethylisoxazol-4-ylsulfonylamino)propionicacid,

3-[7-[(imidazolin-2-ylamino)methyl]-1-methyl-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-(benzyloxycarbonylamino)propionicacid,

3-[7-[(imidazolin-2-ylamino)methyl]-1-methyl-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-(n-butyloxycarbonylamino)propionicacid,

3-[7-[(imidazolin-2-ylamino)methyl]-1-methyl-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-(n-butylsulfonylamino)propionicacid,

3-[7-[(tetrahydropyrimid-2-ylamino)methyl]-1-methyl-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-(benzyloxycarbonylamino)propionicacid,

3-[7-[(tetrahydropyrimid-2-ylamino)methyl]-1-methyl-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-(n-butyloxycarbonylamino)propionicacid,

3-[7-[(tetrahydropyrimid-2-ylamino)methyl]-1-methyl-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-(phenylsulfonylamino)propionicacid,

3-[7-[(tetrahydropyrimid-2-ylamino)methyl]-1-methyl-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-(n-butylsulfonyl)aminopropionicacid,

3-[7-[(2-aminothiazol-4-yl)methyl]-1-methyl-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-(benzyloxycarbonylamino)propionicacid,

3-[7-[(imidazolin-2-ylamino)methyl]-1-methyl-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-((2,4,6-trimethylphenyl)sulfonylamino)propionicacid,

3-[7-[(tetrahydropyrimid-2-ylamino)methyl]-1-methyl-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-((2,4,6-trimethylphenyl)sulfonylamino)propionicacid,

3-[7-[(imidazol-2-ylamino)methyl]-1-methyl-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-(3,5-dimethylisoxazol-4-ylsulfonylamino)propionicacid,

3-[7-[(imidazol-2-ylamino)methyl]-1-methyl-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-(benzyloxycarbonylamino)propionicacid,

3-[7-[(imidazol-2-ylamino)methyl]-1-methyl-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-((2,4,6-trimethylphenyl)sulfonylamino)propionicacid,

3-[7-[(imidazol-2-ylamino)methyl]-1-methyl-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-((4-biphenyl)sulfonylamino)propionicacid,

3-[7-[(imidazol-2-ylamino)methyl]-1-methyl-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-(1-naphthylsulfonylamino)propionicacid,

3-[7-[(benzimidazol-2-ylamino)methyl]-1-methyl-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-((2,4,6-trimethylphenyl)sulfonylamino)propionicacid,

3-[7-[(4-methylimidazol-2-ylamino)methyl]-1-methyl-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-((2,4,6-trimethylphenyl)sulfonylamino)propionicacid,

3-[7-[(4,5-dimethylimidazol-2-ylamino)methyl]-1-methyl-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-((2,4,6-trimethylphenyl)sulfonylamino)propionicacid,

3-[7-[(4,5,6,7-tetrahydrobenzimidazol-2-ylamino)methyl]-1-methyl-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-((2,4,6-trimethylphenyl)sulfonylamino)propionicacid,

3-[7-[(pyridin-2-ylamino)methyl]-1-methyl-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-((2,4,6-trimethylphenyl)sulfonylamino)propionicacid,

3-[7-(2-aminopyridin-6-yl)-1-methyl-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-((2,4,6-trimethylphenyl)sulfonylamino)propionicacid,

3-[7-[(7-azabenzimidazol-2-yl)methyl]-1-methyl-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-((2,4,6-trimethylphenyl)sulfonylamino)propionicacid,

3-[7-[(benzimidazol-2-ylamino)methyl]-1-(2-phenylethyl)-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]propionicacid,

3-[7-[(pyridin-2-ylamino)methyl]-1-(2-phenylethyl)-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]propionicacid,

3-[7-[(imidazolin-2-ylamino)methyl]-1-(2-phenylethyl)-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]propionicacid,

3-[7-[(imidazol-2-ylamino)methyl]-1-(2-phenylethyl)-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]propionicacid,

3-[7-[(imidazolin-2-ylamino)methyl]-1-(2-phenylethyl)-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-(benzyloxycarbonylamino)propionicacid,

3-[7-[(imidazolin-2-ylamino)methyl]-1-(2-phenylethyl)-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-(n-butyloxycarbonylamino)propionicacid,

3-[7-[(imidazolin-2-ylamino)methyl]-1-(2-phenylethyl)-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-(phenylsulfonylamino)propionicacid,

3-[7-[(imidazolin-2-ylamino)methyl]-1-(2-phenylethyl)-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-(n-butylsulfonylamino)propionicacid,

3-[7-[(tetrahydropyrimid-2-ylamino)methyl]-1-(2-phenylethyl)-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-(benzyloxycarbonylamino)propionicacid,

3-[7-[(tetrahydropyrimid-2-ylamino)methyl]-1-(2-phenylethyl)-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-(n-butyloxycarbonylamino)propionicacid,

3-[7-[(tetrahydropyrimid-2-ylamino)methyl]-1-(2-phenylethyl)-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-(phenylsulfonylamino)propionicacid,

3-[7-[(tetrahydropyrimid-2-ylamino)methyl]-1-(2-phenylethyl)-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-(n-butylsulfonyl)aminopropionicacid,

3-[7-[(2-aminothiazol-4-yl)methyl]-1-(2-phenylethyl)-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-(phenylsulfonylamino)propionicacid,

3-[7-[(2-aminothiazol-4-yl)methyl]-1-(2-phenylethyl)-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-(benzyloxycarbonylamino)propionicacid,

3-[7-[(imidazolin-2-ylamino)methyl]-1-(2-phenylethyl)-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-((2,4,6-trimethylphenyl)sulfonylamino)propionicacid,

3-[7-[(tetrahydropyrimid-2-ylamino)methyl]-1-(2-phenylethyl)-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-((2,4,6-trimethylphenyl)sulfonylamino)propionicacid,

3-[7-[(imidazol-2-ylamino)methyl]-1-(2-phenylethyl)-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-(benzyloxycarbonylamino)propionicacid,

3-[7-[(imidazol-2-ylamino)methyl]-1-(2-phenylethyl)-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-(phenylsulfonylamino)propionicacid,

3-[7-[(imidazol-2-ylamino)methyl]-1-(2-phenylethyl)-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-((2,6,dichlorophenyl)sulfonylamino)propionicacid,

3-[7-[(imidazol-2-ylamino)methyl]-1-(2-phenylethyl)-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-((2,4,6-trimethylphenyl)sulfonylamino)propionicacid,

3-[7-[(imidazol-2-ylamino)methyl]-1-(2-phenylethyl)-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-((4-biphenyl)sulfonylamino)propionicacid,

3-[7-[(benzimidazol-2-ylamino)methyl]-1-(2-phenylethyl)-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-((2,4,6-trimethylphenyl)sulfonylamino)propionicacid,

3-[7-[(4-methylimidazol-2-ylamino)methyl]-1-(2-phenylethyl)-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-((2,4,6-trimethylphenyl)sulfonylamino)propionicacid,

3-[7-[(4,5-dimethylimidazol-2-ylamino)methyl]-1-(2-phenylethyl)-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-((2,4,6-trimethylphenyl)sulfonylamino)propionicacid,

3-[7-[(4,5,6,7-tetrahydrobenzimidazol-2-ylamino)methyl]-1-(2-phenylethyl)-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-((2,4,6-trimethylphenyl)sulfonylamino)propionicacid,

3-[7-[(pyridin-2-ylamino)methyl]-1-(2-phenylethyl)-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-((2,4,6-trimethylphenyl)sulfonylamino)propionicacid,

3-[7-(2-aminopyridin-6-yl)-1-(2-phenylethyl)-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-((2,4,6-trimethylphenyl)sulfonylamino)propionicacid,

3-[7-[(7-azabenzimidazol-2-yl)methyl]-1-(2-phenylethyl)-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-((2,4,6-trimethylphenyl)sulfonylamino)propionicacid

[3a] In a third embodiment of the present invention are compounds ofFormula II:

including stereoisomeric forms thereof, or mixtures of stereoisomericforms thereof, or pharmaceutically acceptable salt or prodrug formsthereof wherein:

R¹ is selected from:

A is —CH₂— or —N(R¹²)—;

A¹ and B are independently —CH₂— or —N(R¹⁰)—;

D is —N(R¹²)— or —S—;

E—F is —C(R²)₂C(R³)₂— or —CH(R²)CH(R³)—;

R² and R³ are independently selected from:

H, C₁-C₄ alkoxy, NR¹¹R¹², halogen, NO₂, CN, CF₃, C₁-C₆ alkyl, C₃-C₆alkenyl, C₃-C₇ cycloalkyl,

C₃-C₇ cycloalkyl(C₁-C₄ alkyl), aryl(C₁-C₆ alkyl)-,

(C₁-C₆ alkyl)carbonyl, (C₁-C₆ alkoxy)carbonyl,

arylcarbonyl, and aryl substituted with 0-4 R⁷,

alternatively, when R² and R³ are substituents on adjacent atoms, theycan be taken together with the carbon atoms to which they are attachedto form a 5-7 membered carbocyclic or 5-7 membered heterocyclic aromaticor nonaromatic ring system, said carbocyclic or heterocyclic ring beingsubstituted with 0-2 groups selected from C₁-C₄ alkyl, C₁-C₄ alkoxy,halo, cyano, amino, CF₃ and NO₂;

R^(2a) is selected from:

H, C₁-C₁₀ alkyl, C₂-C₆ alkenyl, C₃-C₁₁ cycloalkyl,

C₃-C₇ cycloalkyl(C₁-C₄ alkyl), aryl, aryl(C₁-C₄ alkyl)-, (C₂-C₇alkyl)carbonyl, arylcarbonyl,

(C₂-C₁₀ alkoxy)carbonyl, C₃-C₇ cycloalkoxycarbonyl,

C₇-C₁₁ bicycloalkoxycarbonyl, aryloxycarbonyl,

aryl(C₁-C₁₀ alkoxy)carbonyl,

C₁-C₆ alkylcarbonyloxy(C₁-C₄ alkoxy)carbonyl,

arylcarbonyloxy(C₁-C₄ alkoxy)carbonyl, and

C₃-C₇ cycloalkylcarbonyloxy (C₁-C₄ alkoxy)carbonyl;

R⁴ is selected from:

H, C₁-C₆ alkyl, C₃-C₇ cycloalkyl, C₃-C₇ cycloalkyl(C₁-C₄ alkyl)-, aryl,heteroaryl, aryl(C₁-C₆ alkyl)-, and

heteroaryl(C₁-C₆ alkyl)-, wherein said aryl or heteroaryl groups aresubstituted with 0-2 substituents independently selected from the groupconsisting of C₁-C₄ alkyl, C₁-C₄ alkoxy, F, Cl, Br, CF₃, and NO₂,

R⁶ is selected from:

H, C₁-C₁₀ alkyl, hydroxy, C₁-C₁₀ alkoxy, nitro, C₁-C₁₀ alkylcarbonyl,—N(R¹¹)R¹², cyano, halo, CF₃, CHO, CO₂R^(18b), C(═O)R^(18b),CONR¹⁷R^(18b), OC(═O)R¹⁰, OR¹⁰, OC(═O)NR¹⁰R¹¹, NR¹⁰C(═O)R¹⁰,NR¹⁰C(═O)OR²¹, NR¹⁰C(═O)NR¹⁰R¹¹, NR¹⁰SO₂NR¹⁰R¹¹, NR¹⁰SO₂R²¹,S(O)_(p)R¹¹, SO₂NR¹⁰R¹¹,

aryl substituted with 0-3 groups selected from halogen, C₁-C₆ alkoxy,C₁-C₆ alkyl, CF₃, S(O)_(m)Me, and —NMe₂,

aryl(C₁-C₄ alkyl)-, said aryl being substituted with 0-3 groups selectedfrom halogen, C₁-C₆ alkoxy, C₁-C₆ alkyl, CF₃, S(O)_(p)Me, and —NMe₂, and

a 5-10 membered heterocyclic ring containing 1-3 N, O, or S heteroatoms,wherein said heterocyclic ring may be saturated, partially saturated, orfully unsaturated, said heterocyclic ring being substituted with 0-2 R⁷;

R⁷ is selected from:

H, hydroxy, C₁-C₄ alkyl, C₁-C₄ alkoxy, aryl, aryl(C₁-C₄ alkyl)-, (C₁-C₄alkyl)carbonyl, CO₂R^(18a), SO₂R¹¹,

SO₂NR¹⁰R¹¹, OR¹⁰, and N(R¹¹)R¹²;

U is selected from:

—(CH₂)_(n)—, —(CH₂)_(n)O(CH₂)_(m)—, —(CH₂)_(n)N(R¹²) (CH₂)_(m)—,—NH(CH₂)_(n), —(CH₂)_(n)C(═O)(CH₂)_(m)—, —(CH₂)_(n)S(O)_(p)(CH₂)_(m)—,—(CH₂)_(n)NHNH(CH₂)_(m)—, —N(R¹⁰)C(═O)—, —NHC(═O)(CH₂)_(n)—,—C(═O)N(R¹⁰)—, and —N(R¹⁰)S(O)_(p)—;

G is N or CR¹⁹;

W is —C(═O)—N(R¹⁰)—(C₁-C₃ alkylene)-, in which the alkylene group issubstituted by R⁸ and by R⁹:

R⁸ and R⁹ are independently selected from:

H, CO₂R^(18b), C(═O)R^(18b), CONR¹⁷R^(18b),

C₁-C₁₀ alkyl substituted with 0-1 R⁶,

C₂-C₁₀ alkenyl substituted with 0-1 R⁶,

C₂-C₁₀ alkynyl substituted with 0-1 R⁶,

C₃-C₈ cycloalkyl substituted with 0-1 R⁶,

C₅-C₆ cycloalkenyl substituted with 0-1 R⁶,

(C₁-C₁₀ alkyl)carbonyl,

C₃-C₁₀ cycloalkyl(C₁-C₄ alkyl)-,

phenyl substituted with 0-3 R⁶,

naphthyl substituted with 0-3 R⁶,

a 5-10 membered heterocyclic ring containing 1-3 N, O, or S heteroatoms,wherein said heterocyclic ring may be saturated, partially saturated, orfully unsaturated, said heterocyclic ring being substituted with 0-2 R⁷,

C₁-C₁₀ alkoxy substituted with 0-2 R⁷,

hydroxy, nitro, —N(R¹⁰)R¹¹, —N(R¹⁶)R¹⁷, aryl(C₀-C₆ alkyl)carbonyl,aryl(C₃-C₆ alkyl), heteroaryl(C₁-C₆ alkyl) , CONR^(18a)R²⁰, SO₂R^(18a),and SO₂NR^(18a)R²⁰,

providing that any of the above alkyl, cycloalkyl, aryl or heteroarylgroups may be unsubstituted or substituted independently with 1-2 R⁷;

R¹⁰ is selected from:

H, CF₃, C₃-C₆ alkenyl, C₃-C₁₁ cycloalkyl, aryl,

(C₃-C₁₁ cycloalkyl)methyl, aryl(C₁-C₄ alkyl), and C₁-C₁₀ alkylsubstituted with 0-2 R⁶;

R¹¹ is selected from:

H, hydroxy, C₁-C₈ alkyl, C₃-C₆ alkenyl, C₃-C₁₁ cycloalkyl, (C₃-C₁₁cycloalkyl)methyl, C₁-C₆ alkoxy,

benzyloxy, aryl, heteroaryl, heteroaryl(C₁-C₄ alkyl)-,

aryl(C₁-C₄ alkyl), adamantylmethyl, and

C₁-C₁₀ alkyl substituted with 0-2 R⁴;

alternatively, when R¹⁰ and R¹¹ are both substituents on the samenitrogen atom (as in —NR¹⁰R¹¹) they may be taken together with thenitrogen atom to which they are attached to form a heterocycle selectedfrom:

3-azabicyclononyl, 1,2,3,4-tetrahydro-1-quinolinyl,1,2,3,4-tetrahydro-2-isoquinolinyl, 1-piperidinyl, 1-morpholinyl,1-pyrrolidinyl, thiamorpholinyl, thiazolidinyl, and 1-piperazinyl;

said heterocycle being substituted with 0-3 groups selected from: C₁-C₆alkyl, aryl, heteroaryl, aryl(C₁-C₄ alkyl)-, (C₁-C₆ alkyl)carbonyl,(C₃-C₇ cycloalkyl)carbonyl, (C₁-C₆ alkoxy)carbonyl, aryl(C₁-C₄alkoxy)carbonyl, C₁-C₆ alkylsulfonyl, and arylsulfonyl;

R¹² is selected from:

H, C₁-C₆ alkyl, triphenylmethyl, methoxymethyl,

methoxyphenyldiphenylmethyl,

trimethylsilylethoxymethyl, (C₁-C₆ alkyl)carbonyl,

(C₁-C₆ alkoxy)carbonyl, (C₁-C₆ alkyl)aminocarbonyl,

C₃-C₆ alkenyl, C₃-C₇ cycloalkyl, C₃-C₇ cycloalkyl(C₁-C₄ alkyl)-, aryl,heteroaryl(C₁-C₆ alkyl)carbonyl,

heteroarylcarbonyl, aryl(C₁-C₆ alkyl)-,

(C₁-C₆ alkyl)carbonyl, arylcarbonyl, C₁-C₆ alkylsulfonyl, arylsulfonyl,aryl(C₁-C₆ alkyl)sulfonyl,

heteroarylsulfonyl, heteroaryl(C₁-C₆ alkyl)sulfonyl,

aryloxycarbonyl, and aryl(C₁-C₆ alkoxy)carbonyl,

wherein said aryl groups are substituted with 0-2 substituents selectedfrom the group consisting of C₁-C₄ alkyl, C₁-C₄ alkoxy, halo, CF₃, andnitro;

R¹⁶ is selected from:

—C(═O)OR^(18a), —C(═O)R^(18b), —C(═O)N(R^(18b))₂, —C(═O)NHSO₂R^(18a),

—C(═O)NHC(═O)R^(18b), —C(═O)NHC(═O)OR^(18a),

—C(═O)NHSO₂NHR^(18b), —SO₂R^(18a), —SO₂N(R^(18b))₂, and

—SO₂NHC(═O)OR^(18b) ;

R¹⁷ is selected from:

H, C₁-C₆ alkyl, C₃-C₇ cycloalkyl, C₃-C₇ cycloalkyl(C₁-C₄ alkyl)-, aryl,aryl(C₁-C₆ alkyl)-, and heteroaryl(C₁-C₆ alkyl);

R^(18a) is selected from:

C₁-C₈ alkyl, C₃-C₁₁ cycloalkyl, aryl(C₁-C₆ alkyl)-, said arylsubstituted with 0-4 R¹⁹,

heteroaryl(C₁-C₆ alkyl)-, said heteroaryl substituted with 0-4 R¹⁹,

(C₁-C₆ alkyl)heteroaryl, said heteroaryl substituted with 0-4 R¹⁹,

heteroaryl substituted with 0-4 R¹⁹,

phenyl substituted with 0-4 R¹⁹, and

naphthyl substituted with 0-4 R¹⁹;

R^(18b) is H or R^(18a);

R¹⁹ is selected from:

H, halogen, CF₃, CO₂H, CN, NO₂, —NR¹¹R^(12,) OCF₃,

C₁-C₈ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl,

C₃-C₁₁ cycloalkyl, C₃-C₇ cycloalkyl(C₁-C₄ alkyl)-,

aryl(C₁-C₆ alkyl)-, C₁-C₆ alkoxy, C₁-C₄ alkoxycarbonyl,

aryl, aryl-O—, aryl-SO₂—, heteroaryl, and

heteroaryl-SO₂—, wherein said aryl and heteroaryl groups are substitutedwith 0-4 groups selected from hydrogen, halogen, CF₃, C₁-C₃ alkyl, andC₁-C₃ alkoxy;

R²⁰ is selected from:

hydroxy, C₁-C₁₀ alkyloxy, C₃-C₁₁ cycloalkyloxy,

aryloxy, aryl(C₁-C₄ alkyl)oxy,

C₂-C₁₀ alkylcarbonyloxy(C₁-C₂ alkyl)oxy-,

C₂-C₁₀ alkoxycarbonyloxy(C₁-C₂ alkyl)oxy-,

C₂-C₁₀ alkoxycarbonyl (C₁-C₂ alkyl)oxy-,

C₃-C₁₀ cycloalkylcarbonyloxy(C₁-C₂ alkyl)oxy - ,

C₃-C₁₀ cycloalkoxycarbonyloxy(C₁-C₂ alkyl)oxy-,

C₃-C₁₀ cycloalkoxycarbonyl (C₁-C₂ alkyl)oxy-,

aryloxycarbonyl(C_(l)-C₂ alkyl)oxy-,

aryloxycarbonyloxy(C₁ -C₂ alkyl)oxy-,

arylcarbonyloxy(C₁-C₂ alkyl)oxy-,

C₁-C₅ alkoxy(C₁-C₅ alkyl)carbonyloxy(C₁-C₂ alkyl)oxy-,

(5-(C₁-C₅ alkyl)-1,3-dioxa-cyclopenten-2-one-yl)methyloxy,

(5-aryl-1,3-dioxa-cyclopenten-2-one-yl)methyloxy, and

(R¹⁰)(R¹¹)N—(C₁-C₁₀ alkoxy)-;

R²¹ is selected from:

C₁-C₈ alkyl, C₂-C₆ alkenyl, C₃-C₁₁ cycloalkyl, (C₃-C₁₁cycloalkyl)methyl, aryl, aryl(C₁-C₄ alkyl)-, and C₁-C₁₀ alkylsubstituted with 0-2 R⁷;

R²² is selected from:

—C(═O)—R^(18b), —C(═O)N(R^(18b))₂, —C(═O)NHSO₂R^(18a),

—C(═O)NHC(═O)R^(18b), —C(═O)NHC(═O)OR^(18a), and

—C (═O)NHSO₂NHR^(18b);

Y is selected from:

—COR²⁰, —SO₃H, —PO₃H, —CONHNHSO₂CF₃, —CONHSO₂R^(18a),

—CONHSO₂NHR^(18b), —NHCOCF₃, —NHCONHSO₂R^(18a), —NHSO₂R^(18a),

—OPO₃H₂, —OSO₃H, —PO₃H₂, —SO₂NHCOR^(18a), —SO₂NHCO₂R^(18a),

m is 0-2;

n is 0-4;

p is 0-2; and

r is 0-2;

with the proviso that n, and m are chosen such that the number of atomsconnecting R¹ and Y is in the range of 8-14.

[3b] Preferred compounds of the third embodiment are those of FormulaIV:

including stereoisomeric forms thereof, or mixtures of stereoisomericforms thereof, or pharmaceutically acceptable salt or prodrug formsthereof wherein:

R¹ is selected from:

A is —CH₂— or —N(R¹²)—;

A¹ and B are independently —CH₂— or —N(R¹⁰)—;

D is —N (R¹²)— or —S—;

E—F is —C(R²)₂C(R³)₂— or —CH(R²)CH(R³)—;

R² and R³ are independently selected from:

H, C₁-C₄ alkoxy, NR¹¹R¹², halogen, NO₂, CN, CF₃, C₁-C₆ alkyl, C₃-C₆alkenyl, C₃-C₇ cycloalkyl,

C₃-C₇ cycloalkyl(C₁-C₄ alkyl), aryl(C₁-C₆ alkyl)-,

(C₁-C₆ alkyl)carbonyl, (C₁-C₆ alkoxy)carbonyl,

arylcarbonyl, and aryl substituted with 0-4 R⁷,

alternatively, when R² and R³ are substituents on adjacent atoms, theycan be taken together with the carbon atoms to which they are attachedto form a 5-7 membered carbocyclic or 5-7 membered heterocyclic aromaticor nonaromatic ring system, said carbocyclic or heterocyclic ring beingsubstituted with 0-2 groups selected from C₁-C₄ alkyl, C₁-C₄ alkoxy,halo, cyano, amino, CF₃ and N₂;

R^(2a) is selected from:

H, C₁-C₁₀ alkyl, C₂-C₆ alkenyl, C₃-C₁₁ cycloalkyl,

C₃-C₇ cycloalkyl(C₁-C₄ alkyl), aryl, aryl(C₁-C₄ alkyl)-, (C₂-C₇alkyl)carbonyl, arylcarbonyl,

(C₂-C₁₀ alkoxy)carbonyl, C₃-C₇ cycloalkoxycarbonyl,

C₇-C₁₁ bicycloalkoxycarbonyl, aryloxycarbonyl,

aryl(C₁-C₁₀ alkoxy)carbonyl,

C₁-C₆ alkylcarbonyloxy(C₁-C₄ alkoxy)carbonyl,

arylcarbonyloxy(C₁-C₄ alkoxy)carbonyl, and C₃-C₇cycloalkylcarbonyloxy(C₁-C₄ alkoxy)carbonyl;

R⁴ is selected from:

H, C₁-C₆ alkyl, C₃-C₇ cycloalkyl, C₃-C₇ cycloalkyl(C₁-C₄ alkyl)-, aryl,heteroaryl, aryl(C₁-C₆ alkyl)-, and

heteroaryl(C₁-C₆ alkyl)-, wherein said aryl or heteroaryl groups aresubstituted with 0-2 substituents independently selected from the groupconsisting of C₁-C₄ alkyl, C₁-C₄ alkoxy, F, Cl, Br, CF₃, and NO₂,

R⁶ is selected from:

H, C₁-C₁₀ alkyl, hydroxy, C₁-C₁₀ alkoxy, nitro, C₁-C₁₀ alkylcarbonyl,—N(R¹¹)R¹², cyano, halo, CF₃, CHO, CO₂R^(18b), C(═O)R^(18b),CONR¹⁷R^(18b), OC(═O)R¹⁰, OR¹⁰, OC(═O)NR¹⁰R¹¹, NR¹⁰C(═O)R¹⁰,NR¹⁰C(═O)OR²¹, NR¹⁰C(═O)NR¹⁰R¹¹, NR¹⁰SO₂NR¹⁰R¹¹, NR¹⁰SO₂R²¹,S(O)_(p)R¹¹, SO₂NR¹⁰R¹¹,

aryl substituted with 0-3 groups selected from halogen, C₁-C₆ alkoxy,C₁-C₆ alkyl, CF₃, S(O)_(m)Me, and —NMe₂,

aryl(C₁-C₄ alkyl)-, said aryl being substituted with 0-3 groups selectedfrom halogen, C₁-C₆ alkoxy, C₁-C₆ alkyl, CF₃, S(O)_(p)Me, and —NMe₂, and

a 5-10 membered heterocyclic ring containing 1-3 N, O, or S heteroatoms,wherein said heterocyclic ring may be saturated, partially saturated, orfully unsaturated, said heterocyclic ring being substituted with 0-2 R⁷;

R⁷ is selected from:

H, hydroxy, C₁-C₄ alkyl, C₁-C₄ alkoxy, aryl, aryl(C₁-C₄ alkyl)-, (C₁-C₄alkyl)carbonyl, CO₂R^(18a), SO₂R¹¹,

SO₂NR¹⁰R¹¹, OR¹⁰, and N(R¹¹)R¹²;

U is selected from:

—(CH₂)_(n)—, —(CH₂)_(n)O(CH₂)_(m)—, —NH(CH₂)_(n)—, —N(R¹⁰)C(═O)—,

—NHC(═O)(CH₂)_(n)—, and —C(═O)N(R¹⁰)—;

G is N or CR¹⁹;

R⁸ is selected from:

H, CO₂R^(18b), C(═O)R^(18b), CONR¹⁷R^(18b),

C₁-C₁₀ alkyl substituted with 0-1 R⁶,

C₂-C₁₀ alkenyl substituted with 0-1 R⁶,

C₂-C₁₀ alkynyl substituted with 0-1 R⁶,

C₃-C₈ cycloalkyl substituted with 0-1 R⁶,

C₅-C₆ cycloalkenyl substituted with 0-1 R⁶,

(C₁-C₁₀ alkyl)carbonyl,

C₃-C₁₀ cycloalkyl(C₁-C₄ alkyl)-,

phenyl substituted with 0-3 R⁶,

naphthyl substituted with 0-3 R⁶,

a 5-10 membered heterocyclic ring containing 1-3 N, O, or S heteroatoms,wherein said heterocyclic ring may be saturated, partially saturated, orfully unsaturated, said heterocyclic ring being substituted with 0-2 R⁷;

R⁹ is selected from:

C₁-C₁₀ alkyl substituted with 0-1 R⁶,

C₁-C₁₀ alkoxy substituted with 0-2 R⁷,

H, nitro, N(R¹¹)R¹², OC(═O)R¹⁰, OR¹⁰, OC(═O)NR¹⁰R¹¹, NR¹⁰C(═O)R¹⁰,NR¹⁰C(═O)OR²¹, NR²C(═O)NR¹⁰R¹¹, NR¹⁰SO₂NR¹⁰R¹¹, NR¹⁰SO₂R²¹, hydroxy,OR²², —N(R¹⁰)R¹¹, —N(R¹⁶)R¹⁷, aryl(C₀-C₆ alkyl)carbonyl, aryl(C₁-C₆alkyl), heteroaryl(C₁-C₆ alkyl), CONR^(18a)R²⁰, SO₂R^(18a), andSO₂NR^(18a)R²⁰,

providing that any of the above alkyl, cycloalkyl, aryl or heteroarylgroups may be unsubstituted or substituted independently with 1-2 R⁷;

R¹⁰ is selected from:

H, CF₃, C₃-C₆ alkenyl, C₃-C₁₁ cycloalkyl, aryl,

(C₃-C₁₁ cycloalkyl)methyl, aryl(C₁-C₄ alkyl), and C₁-C₁₀ alkylsubstituted with 0-2 R⁶;

R¹¹ is selected from:

H, hydroxy, C₁-C₈ alkyl, C₃-C₆ alkenyl, C₃-C₁₁ cycloalkyl, (C₃-C₁₁cycloalkyl)methyl, C₁-C₆ alkoxy,

benzyloxy, aryl, heteroaryl, heteroaryl(C₁-C₄ alkyl)-,

aryl(C₁-C₄ alkyl), adamantylmethyl, and

C₁-C₁₀ alkyl substituted with 0-2 R⁴;

R¹² is selected from:

H, C₁-C₆ alkyl, triphenylmethyl, methoxymethyl,

methoxyphenyldiphenylmethyl,

trimethylsilylethoxymethyl, (C₁-C₆ alkyl)carbonyl,

(C₁-C₆ alkoxy)carbonyl, (C₁-C₆ alkyl)aminocarbonyl,

C₃-C₆ alkenyl, C₃-C₇ cycloalkyl, C₃-C₇ cycloalkyl(C₁-C₄ alkyl)-, aryl,heteroaryl(C₁-C₆ alkyl)carbonyl,

heteroarylcarbonyl, aryl(C₁-C₆ alkyl)-,

(C₁-C₆ alkyl)carbonyl, arylcarbonyl, C₁-C₆ alkylsulfonyl, arylsulfonyl,aryl(C₁-C₆ alkyl)sulfonyl,

heteroarylsulfonyl, heteroaryl(C₁-C₆ alkyl)sulfonyl,

aryloxycarbonyl, and aryl(C₁-C₆ alkoxy)carbonyl,

wherein said aryl groups are substituted with 0-2 substituents selectedfrom the group consisting of C₁-C₄ alkyl, C₁-C₄ alkoxy, halo, CF₃, andnitro;

R¹⁷ is selected from:

H, C₁-C₆ alkyl, C₃-C₇ cycloalkyl, C₃-C₇ cycloalkyl(C₁-C₄ alkyl)-, aryl,aryl(C₁-C₆ alkyl)-, and heteroaryl(C₁-C₆ alkyl);

R^(18a) is selected from:

C₁-C₈ alkyl, C₃-C₁₁ cycloalkyl, aryl(C₁-C₆ alkyl)-, said arylsubstituted with 0-4 R¹⁹,

heteroaryl(C₁-C₆ alkyl)-, said heteroaryl substituted with 0-4 R¹⁹,

(C₁-C₆ alkyl)heteroaryl, said heteroaryl substituted with 0-4 R¹⁹,

heteroaryl substituted with 0-4 R¹⁹,

phenyl substituted with 0-4 R¹⁹, and

naphthyl substituted with 0-4 R¹⁹;

R^(18b) is H or R^(18a);

R¹⁹ is selected from:

H, halogen, CF₃, CO₂H, CN, NO₂, —NR¹¹R¹², OCF₃,

C₁-C₈ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl,

C₃-C₁₁ cycloalkyl, C₃-C₇ cycloalkyl(C₁-C₄ alkyl)-,

aryl(C₁-C₆ alkyl)-, C₁-C₆ alkoxy, C₁-C₄ alkoxycarbonyl,

aryl, aryl-O—, aryl-SO₂—, heteroaryl, and

heteroaryl-SO₂—, wherein said aryl and heteroaryl groups are substitutedwith 0-4 groups selected from hydrogen, halogen, CF₃, C₁-C₃ alkyl, andC₁-C₃ alkoxy;

R²⁰ is selected from:

hydroxy, C₁-C₁₀ alkyloxy, C₃-C₁₁ cycloalkyloxy,

aryloxy, aryl(C₁-C₄ alkyl)oxy,

C₂-C₁₀ alkylcarbonyloxy(C₁-C₂ alkyl)oxy-,

C₂-C₁₀ alkoxycarbonyloxy(C₁-C₂ alkyl)oxy-,

C₂-C₁₀ alkoxycarbonyl(C₁-C₂ alkyl)oxy-,

C₃-C₁₀ cycloalkylcarbonyloxy(C₁-C₂ alkyl)oxy-,

C₃-C₁₀ cycloalkoxycarbonyloxy(C₁-C₂ alkyl)oxy-,

C₃-C₁₀ cycloalkoxycarbonyl(C₁-C₂ alkyl)oxy-,

aryloxycarbonyl(C₁-C₂ alkyl)oxy-,

aryloxycarbonyloxy(C₁-C₂ alkyl)oxy-,

arylcarbonyloxy(C₁-C₂ alkyl)oxy-,

C₁-C₅ alkoxy(C₁-C₅ alkyl)carbonyloxy(C₁-C₂ alkyl)oxy-,

(5-(C₁-C₅ alkyl)-1,3-dioxa-cyclopenten-2-one-yl)methyloxy,

(5-aryl-1,3-dioxa-cyclopenten-2-one-yl)methyloxy, and(R¹⁰)(R¹¹)N—(C₁-C₁₀ alkoxy)-;

R²¹ is selected from:

C₁-C₈ alkyl, C₂-C₆ alkenyl, C₃-C₁₁ cycloalkyl, (C₃-C₁₁cycloalkyl)methyl, aryl, aryl(C₁-C₄ alkyl)-, and C₁-C₁₀ alkylsubstituted with 0-2 R⁷;

R²² is selected from:

—C(═O)R^(18b), —C(═O)N(R^(18b))₂, —C(═O)NHSO₂R^(18a),

—C(═O)NHC(═O)R^(18b), and —C(═O)NHC(═O)OR^(18a);

m is 0-2;

n is 0-4;

p is 0-2; and

r is 0-2;

with the proviso that n and m are chosen such that the number of atomsconnecting R¹ and COR²⁰ of Formula (IV) is in the range of 8-14.

[3c] Preferred compounds of the third embodiment are those of FormulaIV:

including stereoisomeric forms thereof, or mixtures of stereoisomericforms thereof, or pharmaceutically acceptable salt or prodrug formsthereof wherein:

R¹ is selected from:

A is —CH₂— or —N(R¹²)—;

A¹ and B are independently —CH₂— or —N(R¹⁰)—;

D is —N(R¹²)— or —S—;

E—F is —C(R²)₂C(R³)₂— or —CH(R²)CH(R³)₂—;

R² and R³ are independently selected from:

H, C₁-C₄ alkoxy, NR¹¹R¹² halogen, NO₂, CN, CF₃, C₁-C₆ alkyl, C₃-C₆alkenyl, C₃-C₇ cycloalkyl,

C₃-C₇ cycloalkyl (C₁-C₄ alkyl), aryl(C₁-C₆ alkyl)-,

(C₁-C₆ alkyl)carbonyl, (C₁-C₆ alkoxy)carbonyl,

arylcarbonyl, and aryl substituted with 0-4 R⁷,

alternatively, when R² and R³ are substituents on adjacent atoms, theycan be taken together with the carbon atoms to which they are attachedto form a 5-7 membered carbocyclic or 5-7 membered heterocyclic aromaticor nonaromatic ring system, said carbocyclic or heterocyclic ring beingsubstituted with 0-2 groups selected from C₁-C₄ alkyl, C₁-C₄ alkoxy,halo, cyano, amino, CF₃ and NO₂;

R^(2a) is selected from:

H, C₁-C₁₀ alkyl, C₂-C₆ alkenyl, C₃-C₁₁ cycloalkyl,

C₃-C₇ cycloalkyl(C₁-C₄ alkyl), aryl, aryl(C₁-C₄ alkyl)-, (C₂-C₇alkyl)carbonyl, arylcarbonyl,

(C₂-C₁₀ alkoxy)carbonyl, C₃-C₇ cycloalkoxycarbonyl,

C₇-C₁₁ bicycloalkoxycarbonyl, aryloxycarbonyl,

aryl(C₁-C₁₀ alkoxy)carbonyl,

C₁-C₆ alkylcarbonyloxy(C₁-C₄ alkoxy)carbonyl,

arylcarbonyloxy(C₁-C₄ alkoxy)carbonyl, and

C₃-C₇ cycloalkylcarbonyloxy(C₁-C₄ alkoxy)carbonyl;

R⁴ is selected from:

H, C₁-C₆ alkyl, C₃-C₇ cycloalkyl, C₃-C₇ cycloalkyl(C₁-C₄ alkyl)-, aryl,heteroaryl, aryl(C₁-C₆ alkyl)-, and

heteroaryl(C₁-C₆ alkyl)-, wherein said aryl or heteroaryl groups aresubstituted with 0-2 substituents independently selected from the groupconsisting of C₁-C₄ alkyl, C₁-C₄ alkoxy, F, Cl, Br, CF₃, and NO₂,

R⁶ is selected from:

H, C₁-C₁₀ alkyl, hydroxy, C₁-C₁₀ alkoxy, nitro, C₁-C₁₀ alkylcarbonyl,—N(R¹¹)R¹², cyano, halo, CF₃, CHO, CO₂R^(18b), C(═O)R^(18b),CONR¹⁷R^(18b), OC(═O)R¹⁰, OR¹⁰, OC(═O)NR¹⁰OR¹¹, NR¹⁰C(═O)R¹⁰,NR¹⁰C(═O)OR²¹, NR¹⁰C(═O)NR¹⁰R¹¹, NR¹⁰SO₂NR¹⁰OR¹¹, NR¹⁰SO₂R²¹,S(O)_(p)R¹¹, SO₂NR¹⁰R¹¹,

aryl substituted with 0-3 groups selected from halogen, C₁-C₆ alkoxy,C₁-C₆ alkyl, CF₃, S(O)_(m)Me, and —NMe₂,

aryl(C₁-C₄ alkyl)-, said aryl being substituted with 0-3 groups selectedfrom halogen, C₁-C₆ alkoxy, C₁-C₆ alkyl, CF₃, S(O)_(p)Me, and —NMe₂, and

a 5-10 membered heterocyclic ring containing 1-3 N, O, or S heteroatoms,wherein said heterocyclic ring may be saturated, partially saturated, orfully unsaturated, said heterocyclic ring being substituted with 0-2 R⁷;

R⁷ is selected from:

H, hydroxy, C₁-C₄ alkyl, C₁-C₄ alkoxy, aryl, aryl(C₁-C₄ alkyl)-, (C₁-C₄alkyl)carbonyl, CO₂R^(18a), SO₂R¹¹,

SO₂NR¹⁰R¹¹, OR¹⁰, and N(R¹¹)R¹²;

U is selected from:

—(CH₂)_(n)—, —(CH₂)_(n)O(CH₂)_(m)—, —NH(CH₂)_(n)—, —N(R¹⁰)C(═O)—,

—NHC(═O)(CH₂)_(n)—, and —C(═O)N(R¹⁰)—;

G is N or CR¹⁹;

R⁸ is H;

R⁹ is selected from:

H, nitro, N(R¹¹)R¹², OC(═O)R¹⁰, OR¹⁰, OC(═O)NR¹⁰OR¹¹, NR¹⁰C(═O)R¹⁰,NR¹⁰C(═O)OR²¹, NR¹⁰C(═O)NR¹⁰R¹¹, NR¹⁰SO₂NR¹⁰R¹¹, NR¹⁰SO₂R²¹, hydroxy,OR²², —N(R¹⁰)R¹¹, —N(R¹⁶)R¹⁷, aryl(C₁-C₆ alkyl)carbonyl, aryl(C₁-C₆alkyl), heteroaryl(C₁-C₆ alkyl), CONR^(18a)R²⁰, SO₂R^(18a), andSO₂NR^(18a)R²⁰,

providing that any of the above alkyl, cycloalkyl, aryl or heteroarylgroups may be unsubstituted or substituted independently with 1-2 R⁷;

R¹⁰ is selected from:

H, CF₃, C₃-C₆ alkenyl, C₃-C₁₁ cycloalkyl, aryl,

(C₃-C₁₁ cycloalkyl)methyl, aryl(C₁-C₄ alkyl), and C₁-C₁₀ alkylsubstituted with 0-2 R⁶;

R¹¹ is selected from:

H, hydroxy, C₁-C₈ alkyl, C₃-C₆ alkenyl, C₃-C₁₁ cycloalkyl, (C₃-C₁₁cycloalkyl)methyl, C₁-C₆ alkoxy,

benzyloxy, aryl, heteroaryl, heteroaryl(C₁-C₄ alkyl)-,

aryl(C₁-C₄ alkyl), adamantylmethyl, and

C₁-C₁₀ alkyl substituted with 0-2 R⁴;

R¹² is selected from:

H, C₁-C₄ alkyl, (C₁-C₄ alkyl)carbonyl, (C₁-C₄ alkoxy)carbonyl,phenyl(C₁-C₄ alkyl)-, phenylsulfonyl,

phenyloxycarbonyl, and phenyl(C₁-C₄ alkoxy)carbonyl,

wherein said phenyl groups are substituted with 0-2 substituentsselected from the group consisting of C₁-C₄ alkyl, C₁-C₄ alkoxy, halo,CF₃, and nitro;

R¹⁷ is selected from:

H, C₁-C₆ alkyl, C₃-C₇ cycloalkyl, C₃-C₇ cycloalkyl(C₁-C₄ alkyl)-, aryl,aryl(C₁-C₆ alkyl)-, and heteroaryl(C₁-C₆ alkyl);

R^(18a) is selected from:

C₁-C₈ alkyl, C₃-C₁₁ cycloalkyl,

aryl(C₁-C₆ alkyl)-, said aryl substituted with 0-4 R¹⁹,

heteroaryl(C₁-C₆ alkyl)-, said heteroaryl substituted with 0-4 R¹⁹,

(C₁-C₆ alkyl)heteroaryl, said heteroaryl substituted with 0-4 R¹⁹,

heteroaryl substituted with 0-4 R¹⁹,

phenyl substituted with 0-4 R¹⁹, and

naphthyl substituted with 0-4 R¹⁹;

R^(18b) is H or R^(18a);

R¹⁹ is selected from:

H, halogen, CF₃, CO₂H, CN, NO₂, —NR¹¹R¹², OCF₃,

C₁-C₈ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl,

C₃-C₁₁ cycloalkyl, C₃-C₇ cycloalkyl(C₁-C₄

alkyl)-,

aryl(C₁-C₆ alkyl)-, C₁-C₆ alkoxy, C₁-C₄ alkoxycarbonyl,

aryl, aryl-O—, aryl-SO₂—, heteroaryl, and

heteroaryl-SO₂—, wherein said aryl and heteroaryl groups are substitutedwith 0-4 groups selected from hydrogen, halogen, CF₃, C₁-C₃ alkyl, andC₁-C₃ alkoxy;

R²⁰ is selected from:

hydroxy, C₁-C₁₀ alkyloxy, C₃-C₁₁ cycloalkyloxy,

aryloxy, aryl(C₁-C₄ alkyl)oxy,

C₂-C₁₀ alkylcarbonyloxy(C₁-C₂ alkyl)oxy-,

C₂-C₁₀ alkoxycarbonyloxy(C₁-C₂ alkyl)oxy-,

C₂-C₁₀ alkoxycarbonyl(C₁-C₂ alkyl)oxy-,

C₃-C₁₀ cycloalkylcarbonyloxy(C₁-C₂ alkyl)oxy-,

C₃-C₁₀ cycloalkoxycarbonyloxy(C₁-C₂ alkyl)oxy-,

C₃-C₁₀ cycloalkoxycarbonyl(C₁-C₂ alkyl)oxy-,

aryloxycarbonyl(C₁-C₂ alkyl)oxy-,

aryloxycarbonyloxy(C₁-C₂ alkyl)oxy-,

arylcarbonyloxy(C₁-C₂ alkyl)oxy-,

C₁-C₅ alkoxy(C₁-C₅ alkyl)carbonyloxy(C₁-C₂ alkyl)oxy-,

(5-(C₁-C₅ alkyl)-1,3-dioxa-cyclopenten-2-one-yl)methyloxy,

(5-aryl-1,3-dioxa-cyclopenten-2-one-yl)methyloxy, and(R¹⁰)(R¹¹)N—(C₁-C₁₀ alkoxy)-;

R²¹ is selected from:

C₁-C₈ alkyl, C₂-C₆ alkenyl, C₃-C₁₁ cycloalkyl, (C₃-C₁₁cycloalkyl)methyl, aryl, aryl(C₁-C₄ alkyl)-, and C₁-C₁₀ alkylsubstituted with 0-2 R⁷;

R²² is selected from:

—C(═O)R^(18b), —C(═O)N(R^(18b))₂, —C(═O)NHSO₂R^(18a),

—C(═O)NHC(═O)R^(18b), and —C(═O)NHC(═O)OR^(18a);

m is 0-2;

n is 0-4;

p is 0-2; and

r is 0-2;

with the proviso that n and m are chosen such that the number of atomsconnecting R¹ and COR²⁰ of Formula (IV) is in the range of 8-14.

[3d] Specifically preferred compounds of the above invention arecompounds of Formula IV including enantiomeric or diastereomeric formsthereof, or mixtures of enantiomeric or diastereomeric forms thereof, orpharmaceutically acceptable salt or prodrug forms thereof selected fromthe group consisting of:

3-[7-[(imidazolin-2-ylamino)methyl]-1-methylquinoline-4-one-3-ylcarbonylamino]-2-(3,5-dimethylisoxazol-4-ylsulfonylamino)propionicacid,

3-[7-[(imidazolin-2-ylamino)methyl]-1-methylquinoline-4-one-3-ylcarbonylamino]-2-(benzyloxycarbonylamino)propionicacid,

3-[7-[(imidazolin-2-ylamino)methyl]-1-methylquinoline-4-one-3-ylcarbonylamino]-2-(n-butyloxycarbonylamino)propionicacid,

3-[7-[(imidazolin-2-ylamino)methyl]-1-methylquinoline-4-one-3-ylcarbonylamino]-2-(n-butylsulfonylamino)propionicacid,

3-[7-[(imidazolin-2-ylamino)methyl]-1-methylquinoline-4-one-3-ylcarbonylamino]-2-((2,4,6-trimethylphenyl)sulfonylamino)propionicacid,

3-[7-[(imidazolin-2-ylamino)methyl]-1-(2-phenylethyl)quinoline-4-one-3-ylcarbonylamino]-2-(benzyloxycarbonylamino)propionicacid,

3-[7-[(imidazolin-2-ylamino)methyl]-1-(2-phenylethyl)quinoline-4-one-3-ylcarbonylamino]-2-(n-butyloxycarbonyl-amino)propionicacid,

3-[7-[(imidazolin-2-ylamino)methyl]-1-(2-phenylethyl)quinoline-4-one-3-ylcarbonylamino]-2-(phenylsulfonylamino)propionicacid,

3-[7-[(imidazolin-2-ylamino)methyl]-1-(2-phenylethyl)quinoline-4-one-3-ylcarbonylamino]-2-(n-butylsulfonylamino)propionicacid,

3-[7-[(imidazolin-2-ylamino)methyl]-1-(2-phenylethyl)quinoline-4-one-3-ylcarbonylamino]-2-((2,4,6-trimethylphenyl)sulfonylamino)propionicacid,

3-[7-[(tetrahydropyrimid-2-ylamino)methyl]-1-methylquinoline-4-one-3-ylcarbonylamino]-2-(benzyloxycarbonylamino)propionicacid,

3-[7-[(tetrahydropyrimid-2-ylamino)methyl]-1-(2-phenylethyl)quinoline-4-one-3-ylcarbonylamino]-2-(n-butyloxycarbonylamino)propionicacid,

3-[7-[(tetrahydropyrimid-2-ylamino)methyl]-1-(2-phenylethyl)quinoline-4-one-3-ylcarbonylamino]-2-(phenylsulfonylamino)propionicacid,

3-[7-[(tetrahydropyrimid-2-ylamino)methyl]-1-methylquinoline-4-one-3-ylcarbonylamino]-2-(n-butylsulfonyl)aminopropionicacid,

3-[7-[(tetrahydropyrimid-2-ylamino)methyl]-1-methylquinoline-4-one-3-ylcarbonylamino]-2-((2,4,6-trimethylphenyl)sulfonylamino)propionicacid,

3-[7-[(tetrahydropyrimid-2-ylamino)methyl]-1-(2-phenylethyl)quinoline-4-one-3-ylcarbonylamino]-2-(benzyloxycarbonylamino)propionicacid,

3-[7-[(tetrahydropyrimid-2-ylamino)methyl]-1-(2-phenylethyl)quinoline-4-one-3-ylcarbonylamino]-2-(n-butyloxycarbonylamino)propionicacid,

3-[7-[(tetrahydropyrimid-2-ylamino)methyl]-1-(2-phenylethyl)quinoline-4-one-3-ylcarbonylamino]-2-(phenylsulfonylamino)propionicacid,

3-[7-[(tetrahydropyrimid-2-ylamino)methyl]-1-(2-phenylethyl)quinoline-4-one-3-ylcarbonylamino]-2-(n-butylsulfonylamino)propionicacid,

3-[7-[(tetrahydropyrimid-2-ylamino)methyl]-1-(2-phenylethyl)quinoline-4-one-3-ylcarbonylamino]-2-((2,4,6-trimethylphenyl)sulfonylamino)propionicacid

3-[7-[(imidazolin-2-ylamino)methyl]-1-methyl-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-(benzyloxycarbonylamino)propionicacid,

3-[7-[(imidazolin-2-ylamino)methyl]-1-methyl-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-(n-butyloxycarbonylamino)propionicacid,

3-[7-[(imidazolin-2-ylamino)methyl]-1-methyl-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-(n-butylsulfonylamino)propionicacid,

3-[7-[(imidazolin-2-ylamino)methyl]-1-methyl-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-((2,4,6-trimethylphenyl)sulfonylamino)propionicacid,

3-[7-[(imidazolin-2-ylamino)methyl]-1-(2-phenylethyl)-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-(benzyloxycarbonylamino)propionicacid,

3-[7-[(imidazolin-2-ylamino)methyl]-1-(2-phenylethyl)-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-(n-butyloxycarbonylamino)propionicacid,

3-[7-[(imidazolin-2-ylamino)methyl]-1-(2-phenylethyl)-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-(phenylsulfonylamino)propionicacid,

3-[7-[(imidazolin-2-ylamino)methyl]-1-(2-phenylethyl)-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-(n-butylsulfonylamino)propionicacid,

3-[7-[(imidazolin-2-ylamino)methyl]-1-(2-phenylethyl)-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-((2,4,6-trimethylphenyl)sulfonylamino)propionicacid,

3-[7-[(tetrahydropyrimid-2-ylamino)methyl]-1-methyl-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-(benzyloxycarbonylamino)propionicacid,

3-[7-[(tetrahydropyrimid-2-ylamino)methyl]-1-(2-phenylethyl)-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-(n-butyloxycarbonylamino)propionicacid,

3-[7-[(tetrahydropyrimid-2-ylamino)methyl]-1-(2-phenylethyl)-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-(phenylsulfonylamino)propionicacid,

3-[7-[(tetrahydropyrimid-2-ylamino)methyl]-1-methylquinoline-4-one-3-ylcarbonylamino]-2-(n-butylsulfonyl)aminopropionicacid,

3-[7-[(tetrahydropyrimid-2-ylamino)methyl]-1-methyl-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-((2,4,6-trimethylphenyl)sulfonylamino)propionicacid,

3-[7-[(tetrahydropyrimid-2-ylamino)methyl]-1-(2-phenylethyl)-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-(benzyloxycarbonylamino)propionicacid,

3-[7-[(tetrahydropyrimid-2-ylamino)methyl]-1-(2-phenylethyl)-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-(n-butyloxycarbonylamino)propionicacid,

3-[7-[(tetrahydropyrimid-2-ylamino)methyl]-1-(2-phenylethyl)-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-(phenylsulfonylamino)propionicacid,

3-[7-[(tetrahydropyrimid-2-ylamino)methyl]-1-(2-phenylethyl)-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-(n-butylsulfonylamino)propionicacid,

3-[7-[(tetrahydropyrimid-2-ylamino)methyl]-1-(2-phenylethyl)-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-((2,4,6-trimethylphenyl)sulfonylamino)propionicacid

[4a] In a fourth embodiment of the present invention are preferredcompounds of Formula II:

including stereoisomeric forms thereof, or mixtures of stereoisomericforms thereof, or pharmaceutically acceptable salt or prodrug formsthereof wherein:

R¹ is selected from:

A is —CH₂— or —N(R¹²)—;

A¹ and B are independently —CH₂— or —N(R¹⁰)—;

D is —N(R¹²)— or —S—;

E—F is —C(R²)═C(R³)— or —C(R²)₂C(R³)₂—;

J is —C(R²)— or —N—;

K, L and M are independently —C(R²)— or —C(R³)—;

R² and R³ are independently selected from:

H, C₁-C₄ alkoxy, NR¹¹R¹², halogen, NO₂, CN, CF₃, C₁-C₆ alkyl, C₃-C₆alkenyl, C₃-C₇ cycloalkyl,

C₃-C₇ cycloalkyl(C₁-C₄ alkyl), aryl(C₁-C₆ alkyl)-,

(C₁-C₆ alkyl)carbonyl, (C₁-C₆ alkoxy)carbonyl,

arylcarbonyl, and aryl substituted with 0-4 R⁷,

alternatively, when R² and R³ are substituents on adjacent atoms, theycan be taken together with the carbon atoms to which they are attachedto form a 5-7 membered carbocyclic or 5-7 membered heterocyclic aromaticor nonaromatic ring system, said carbocyclic or heterocyclic ring beingsubstituted with 0-2 groups selected from C₁-C₄ alkyl, C₁-C₄ alkoxy,halo, cyano, amino, CF₃ and NO₂;

R^(2a) is selected from:

H, C₁-C₁₀ alkyl, C₂-C₆ alkenyl, C₃-C₁₁ cycloalkyl,

C₃-C₇ cycloalkyl(C₁-C₄ alkyl), aryl, aryl(C₁-C₄ alkyl)-, (C₂-C₇alkyl)carbonyl, arylcarbonyl,

(C₂-C₁₀ alkoxy)carbonyl, C₃-C₇ cycloalkoxycarbonyl,

C₇-C₁₁ bicycloalkoxycarbonyl, aryloxycarbonyl,

aryl(C₁-C₁₀ alkoxy)carbonyl,

C₁-C₆ alkylcarbonyloxy(C₁-C₄ alkoxy)carbonyl,

arylcarbonyloxy(C₁-C₄ alkoxy)carbonyl, and

C₃-C₇ cycloalkylcarbonyloxy(C₁-C₄ alkoxy)carbonyl;

R⁴ is selected from:

H, C₁-C₆ alkyl, C-cycloalkyl, C₃-C₇ cycloalkyl(C₁-C₄ alkyl)-, aryl,heteroaryl, aryl(C₁-C₆ alkyl)-, and

heteroaryl(C₁-C₆ alkyl)-, wherein said aryl or heteroaryl groups aresubstituted with 0-2 substituents independently selected from the groupconsisting of C₁-C₄ alkyl, C₁-C₄ alkoxy, F, Cl, Br, CF₃, and NO₂,

R⁶ is selected from:

H, C₁-C₁₀ alkyl, hydroxy, C₁-C₁₀ alkoxy, nitro, C₁-C₁₀ alkylcarbonyl,—N(R¹¹)R¹², cyano, halo, CF₃, CHO, CO₂R^(18b), C(═O)R^(18b),CONR¹⁷R^(18b), OC(═O)R¹⁰, OR¹⁰, OC(═O)NR¹⁰OR¹¹, NR¹⁰C(═O)R¹⁰,NR¹⁰C(═O)OR²¹, NR¹⁰C(═O)NR¹⁰R¹¹, NR¹⁰SO₂NR¹⁰R¹¹, NR¹⁰SO₂R²¹,S(O)_(p)R¹¹, SO₂NR¹⁰R¹¹,

aryl substituted with 0-3 groups selected from halogen, C₁-C₆ alkoxy,C₁-C₆ alkyl, CF₃, S(O)_(m)Me, and —NMe₂,

aryl(C₁-C₄ alkyl)-, said aryl being substituted with 0-3 groups selectedfrom halogen, C₁-C₆ alkoxy, C₁-C₆ alkyl, CF₃, S(O)_(p)Me, and —NMe₂, and

a 5-10 membered heterocyclic ring containing 1-3 N, O, or S heteroatoms,wherein said heterocyclic ring may be saturated, partially saturated, orfully unsaturated, said heterocyclic ring being substituted with 0-2 R⁷;

R⁷ is selected from:

H, hydroxy, C₁-C₄ alkyl, C₁-C₄ alkoxy, aryl, aryl(C₁-C₄ alkyl)-, (C₁-C₄alkyl)carbonyl, CO₂R^(18a), SO₂R¹¹,

SO₂NR¹⁰R¹¹, OR¹⁰, and N(R¹¹)R¹²;

U is selected from:

—(CH₂)_(n)—, —(CH₂)_(n)O(CH₂)_(m)—, —(CH₂)_(n)N(R¹²)(CH₂)_(m)—,

—NH(CH₂)_(n)—, —N(R¹⁰)C(═O)—, —NHC(═O)(CH₂)_(n)—,

—C(═O)N(R¹⁰)—, and —N(R¹⁰)S(O)_(p)—;

G is N or CR¹⁹;

W is —C(═O)—N(R¹⁰)—(C₁-C₃ alkylene)-, in which the alkylene group issubstituted by R⁸ and by R⁹:

R⁸ is selected from:

H, C₁-C₄ alkyl, hydroxy, C₁-C₄ alkoxy, halo, CF₃, CO₂H, NR¹⁰SO₂R²¹,pyridyl, —N(R¹⁶)R¹⁷,

phenyl substituted with 0-3 groups selected from halogen, C₁-C₄ alkoxy,C₁-C₄ alkyl, CF₃, S(O)_(m)Me, and —NMe₂;

phenyl(C₁-C₄ alkyl), said phenyl being substituted with 0-3 groupsselected from halogen, C₁-C₄ alkoxy, C₁-C₄ alkyl, CF₃, S(O)_(p)Me, and—NMe₂, and

carboxy(C₁-C₃ alkyl)-;

R⁹ is selected from:

H, CO₂R^(18b), C(═O)R^(18b), CONR¹⁷R^(18b),

C₁-C₆ alkyl substituted with 0-1 R⁶,

C₂-C₄ alkenyl substituted with 0-1 R⁶,

C₂-C₄ alkynyl substituted with 0-1 R⁶,

C₃-C₈ cycloalkyl substituted with 0-1 R⁶,

C₅-C₆ cycloalkenyl substituted with 0-1 R⁶,

(C₁-C₄ alkyl)carbonyl,

C₃-C₁₀ cycloalkyl(C₁-C₄ alkyl)-,

phenyl substituted with 0-3 R⁶,

naphthyl substituted with 0-3 R⁶,

a 5-10 membered heterocyclic ring containing 1-3 N, O, or S heteroatoms,wherein said heterocyclic ring may be saturated, partially saturated, orfully unsaturated, said heterocyclic ring being substituted with 0-2 R⁷,

C₁-C₄ alkoxy substituted with 0-2 R⁷,

hydroxy, C₀ ₂H, nitro, —N(R¹⁰)R¹¹, —N(R¹⁶)R¹⁷, phenyl(C₀-C₄alkyl)carbonyl, phenyl(C₁-C₄ alkyl)-, heteroaryl(C₁-C₆ alkyl)-,CONR^(18a)R²⁰, SO₂R^(18a), and SO₂NR^(18a)R²⁰,

providing that any of the above alkyl, cycloalkyl, phenyl or heteroarylgroups may be unsubstituted or substituted independently with 1-2 R⁷;

R¹⁰ is selected from:

H, CF₃, C₃-C₆ alkenyl, C₃-C₁₁ cycloalkyl, phenyl,

(C₃-C₁₁ cycloalkyl)methyl, phenyl(C₁-C₄ alkyl), and

C₁-C₁₀ alkyl substituted with 0-2 R⁶;

R¹¹ is selected from:

H, hydroxy, C₁-C₈ alkyl, C₃-C₆ alkenyl, C₃—C₁₁ cycloalkyl, (C₃-C₁₁cycloalkyl)methyl, C₁-C₆ alkoxy,

benzyloxy, aryl, heteroaryl, heteroaryl(C₁-C₄ alkyl)-,

aryl(C_(l)-C₄ alkyl), adamantylmethyl, and

C₁-C₁₀ alkyl substituted with 0-2 R⁴;

alternatively, when R¹⁰ and R¹¹ are both substituents on the samenitrogen atom (as in —NR¹⁰R¹¹) they may be taken together with thenitrogen atom to which they are attached to form a heterocycle selectedfrom:

3-azabicyclononyl, 1,2,3,4-tetrahydro-1-quinolinyl,1,2,3,4-tetrahydro-2-isoquinolinyl, 1-piperidinyl, 1-morpholinyl,1-pyrrolidinyl, thiamorpholinyl, thiazolidinyl, and 1-piperazinyl;

said heterocycle being substituted with 0-3 groups selected from: C₁-C₆alkyl, aryl, heteroaryl, aryl(C₁-C₄ alkyl)-, (C₁-C₆ alkyl)carbonyl,(C₃-C₇ cycloalkyl)carbonyl, (C₁-C₆ alkoxy)carbonyl, aryl(C₁-C₄alkoxy)carbonyl, C₁-C₆ alkylsulfonyl, and arylsulfonyl;

R¹² is selected from:

H, C₁-C₆ alkyl, triphenylmethyl, methoxymethyl,

methoxyphenyldiphenylmethyl,

trimethylsilylethoxymethyl, (C₁-C₆ alkyl)carbonyl,

(C₁-C₆ alkoxy)carbonyl, (C₁-C₆ alkyl)aminocarbonyl,

C₃-C₄ alkenyl, C₃-C₇ cycloalkyl, C₃-C₇ cycloalkyl(C₁-C₄ alkyl)-, aryl,heteroaryl(C₁-C₆ alkyl)carbonyl,

heteroarylcarbonyl, aryl(C₁-C₆ alkyl)-,

(C₁-C₆ alkyl)carbonyl, arylcarbonyl, C₁-C₆ alkylsulfonyl, arylsulfonyl,aryl(C₁-C₆ alkyl)sulfonyl,

heteroarylsulfonyl, heteroaryl(C₁-C₆ alkyl)sulfonyl,

aryloxycarbonyl, and aryl(C₁-C₆ alkoxy)carbonyl,

wherein said aryl groups are substituted with 0-2 substituents selectedfrom the group consisting of C₁-C₄ alkyl, C₁-C₄ alkoxy, halo, CF₃, andnitro;

R¹⁴ is selected from:

H, C₁-C₄ alkyl, and phenyl(C₁-C₄ alkyl);

R¹⁶ is selected from:

—C(═O)OR^(18a), C(═O)R^(18b), —C(═O)N(R^(18b))₂, —C(═O)NHSO₂R^(18a),

—C(═O)NHC(═O)R^(18b), —C(═O)NHC(═O)OR^(18a),

—C(═O)NHSO₂NHR^(18b), —SO₂R^(18a), —SO₂N(R^(18b))₂, and

—SO₂NHC(═O)OR^(18b);

R¹⁷ is selected from:

H, C₁-C₆ alkyl, C₃-C₇ cycloalkyl, C₃-C₇ cycloalkyl(C₁-C₄ alkyl)-, aryl,aryl(C₁-C₆ alkyl)-, and heteroaryl(C₁-C₆ alkyl);

R^(18a) is selected from:

C₁-C₆ alkyl, aryl-, fluoro(C₃-C₆ alkyl), aryl(C₁-C₄ alkyl-, di(C₁-C₄alkyl)amino(C₁-C₄ alkyl),

morpholino(C₁-C₄ alkyl), piperidino(C₁-C₄ alkyl), N—(C₁-C₄alkyl)piperidino(C₁-C₄ alkyl), and phenyl substituted by one or twooptional groups selected from C₁-C₄ alkyl, C₁-C₄ alkoxy, and halogen;

R^(18b) is H or R^(18a);

R¹⁹ is selected from:

H, halogen, CF₃, CO₂H, CN, NO₂, —NR¹¹R¹², OCF₃,

C₁-C₈ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl,

C₃-C₁₁ cycloalkyl, C₃-C₇ cycloalkyl(C₁-C₄ alkyl)-,

aryl(C₁-C₆ alkyl)-, C₁-C₆ alkoxy, C₁-C₄ alkoxycarbonyl,

aryl, aryl-O—, aryl-SO₂—, heteroaryl, and

heteroaryl-SO₂—, wherein said aryl and heteroaryl groups are substitutedwith 0-4 groups selected from hydrogen, halogen, CF₃, C₁-C₃ alkyl, andC₁-C₃ alkoxy;

R²⁰ is selected from:

hydroxy, C₁-C₁₀ alkyloxy, C₃-C₁₁ cycloalkyloxy,

aryloxy, aryl(C₁-C₄ alkyl)oxy,

C₂-C₁₀ alkylcarbonyloxy(C₁-C₂ alkyl)oxy-,

C₂-C₁₀ alkoxycarbonyloxy(C₁-C₂ alkyl)oxy-,

C₂-C₁₀ alkoxycarbonyl(C₁-C₂ alkyl)oxy-,

C₃-C₁₀ cycloalkylcarbonyloxy(C₁-C₂ alkyl)oxy-,

C₃-C₁₀ cycloalkoxycarbonyloxy(C₁-C₂ alkyl)oxy-,

C₃-C₁₀cycloalkoxycarbonyl(C₁-C₂ alkyl)oxy-,

aryloxycarbonyl(C₁-C₂ alkyl)oxy-,

aryloxycarbonyloxy(C₁-C₂ alkyl)oxy-,

arylcarbonyloxy(C₁-C₂ alkyl)oxy-,

C₁-C₅ alkoxy(C₁-C₅ alkyl)carbonyloxy(C₁-C₂ alkyl)oxy-,

(5-(C₁-C₅ alkyl)-1,3-dioxa-cyclopenten-2-one-yl)methyloxy,

(5-aryl-1,3-dioxa-cyclopenten-2-one-yl)methyloxy, and

(R¹⁰)(R¹¹)N—(C₁-C₁₀ alkoxy)-;

R²¹ is selected from:

C₁-C₈ alkyl, C₂-C₆ alkenyl, C₃-C₁₁ cycloalkyl, (C₃-C₁₁cycloalkyl)methyl, aryl, aryl(C₁-C₄ alkyl)-, and C₁-C₁₀ alkylsubstituted with 0-2 R⁷;

Y is selected from:

—COR²⁰, —CONHNHSO₂CF₃, —CONHSO₂R^(18a), —CONHSO₂NHR^(18b) ,

—NHCOCF₃, and —NHSO₂R^(18a);

m is 0-2;

n is 0-4;

p is 0-2;

r is 0-2;

with the proviso that n and m are chosen such that the number of atomsconnecting R¹ and Y is in the range of 8-14.

[4b] Preferred compounds of the fourth embodiment of the presentinvention are those of Formula III:

including stereoisomeric forms thereof, or mixtures of stereoisomericforms thereof, or pharmaceutically acceptable salt or prodrug formsthereof wherein:

R¹ is selected from:

A is —CH₂— or —N(R¹²)—;

A¹ and B are independently —CH₂— or —N(R¹⁰)—;

D is —N(R¹²)— or —S—;

E—F is —C(R²)═C(R³)— or —C(R²)₂C(R³)₂—;

R² and R³ are independently selected from:

H, C₁-C₄ alkoxy, NR¹¹R¹², halogen, NO₂, CN, CF₃, C₁-C₆ alkyl, C₃-C₆alkenyl, C₃-C₇ cycloalkyl,

C₃-C₇ cycloalkyl(C₁-C₄ alkyl), aryl(C₁-C₆ alkyl)-,

(C₁-C₆ alkyl)carbonyl, (C₁-C₆ alkoxy)carbonyl,

arylcarbonyl, and aryl substituted with 0-4 R⁷,

alternatively, when R² and R³ are substituents on adjacent atoms, theycan be taken together with the carbon atoms to which they are attachedto form a 5-7 membered carbocyclic or 5-7 membered heterocyclic aromaticor nonaromatic ring system, said carbocyclic or heterocyclic ring beingsubstituted with 0-2 groups selected from C₁-C₄ alkyl, C₁-C₄ alkoxy,halo, cyano, amino, CF₃ and N₂;

R^(2a) is selected from:

H, C₁-C₁₀ alkyl, C₂-C₆ alkenyl, C₃-C₁₁ cycloalkyl,

C₃-C₇ cycloalkyl(C₁-C₄ alkyl), aryl, aryl(C₁-C₄ alkyl)-,

(C₂-C₇alkyl)carbonyl, arylcarbonyl,

(C₂-C₁₀ alkoxy)carbonyl, C₃-C₇ cycloalkoxycarbonyl,

C₇-C₁₁ bicycloalkoxycarbonyl, aryloxycarbonyl,

aryl(C₁-C₁₀ alkoxy)carbonyl,

C₁-C₆ alkylcarbonyloxy(C₁-C₄ alkoxy)carbonyl,

arylcarbonyloxy(C₁-C₄ alkoxy)carbonyl, and

C₃-C₇ cycloalkylcarbonyloxy(C₁-C₄ alkoxy)carbonyl;

R⁴ is selected from:

H, C₁-C₆ alkyl, C₃-C₇ cycloalkyl, C₃-C₇ cycloalkyl(C₁-C₄ alkyl)-, aryl,heteroaryl, aryl(C₁-C₆ alkyl)-, and

heteroaryl(C₁-C₆ alkyl)-, wherein said aryl or heteroaryl groups aresubstituted with 0-2 substituents independently selected from the groupconsisting of C₁-C₄ alkyl, C₁-C₄ alkoxy, F, Cl, Br, CF₃, and NO₂,

R⁶ is selected from:

H, C₁-C₁₀ alkyl, hydroxy, C₁-C₁₀ alkoxy, nitro, C₁-C₁₀ alkylcarbonyl,—N(R¹¹)R¹², cyano, halo, CF₃, CHO, CO₂R^(18b), C(═O)R^(18b),CONR¹⁷R^(18b), OC(═O)R¹⁰, OR¹⁰, OC(═O)NR¹⁰R¹¹, NR¹⁰C(═O)R¹⁰,NR¹⁰C(═O)OR²¹, NR¹⁰C(═O)NR¹⁰R¹¹, NR¹⁰SO₂NR¹⁰R¹¹, NR¹⁰SO₂R²¹,S(O)_(p)R¹¹, SO₂NR¹⁰R¹¹,

aryl substituted with 0-3 groups selected from halogen, C₁-C₆ alkoxy,C₁-C₆ alkyl, CF₃, S(O)_(m)Me, and —NMe₂,

aryl(C₁-C₄ alkyl)-, said aryl being substituted with 0-3 groups selectedfrom halogen, C₁-C₆ alkoxy, C₁-C₆ alkyl, CF₃, S(O)_(p)Me, and —NMe₂, and

a 5-10 membered heterocyclic ring containing 1-3 N, O, or S heteroatoms,wherein said heterocyclic ring may be saturated, partially saturated, orfully unsaturated, said heterocyclic ring being substituted with 0-2 R⁷;

R⁷ is selected from:

H, hydroxy, C₁-C₄ alkyl, C₁-C₄ alkoxy, aryl, aryl(C₁-C₄ alkyl)-, (C₁-C₄alkyl)carbonyl, CO₂R^(18a), SO₂R¹¹,

SO₂NR¹⁰R¹¹, OR¹⁰, and N(R¹¹)R¹²;

U is selected from:

—(CH₂)_(n)—, —(CH₂)_(n)O(CH₂)_(m)—, —(CH₂)_(n)N(R¹²)(CH₂)_(m)—,

—NH(CH₂)_(n)—, —N(R¹⁰)C(═O)—, and —NHC(═O)(CH₂)_(n)—;

G is N or CR¹⁹;

R⁸ is H;

R⁹ is selected from:

H, CO₂R^(18b), C(═O)R^(18b), CONR¹⁷R^(18b),

C₁-C₆ alkyl substituted with 0-1 R⁶,

C₂-C₄ alkenyl substituted with 0-1 R⁶,

C₂-C₄ alkynyl substituted with 0-1 R⁶,

C₃-C₈ cycloalkyl substituted with 0-1 R⁶,

C₅-C₆ cycloalkenyl substituted with 0-1 R⁶,

(C₁-C₄ alkyl)carbonyl,

C₃-C₁₀ cycloalkyl(C₁-C₄ alkyl)-,

phenyl substituted with 0-3 R⁶,

naphthyl substituted with 0-3 R⁶,

a 5-10 membered heterocyclic ring containing 1 -3 N, O, or Sheteroatoms, wherein said heterocyclic ring may be saturated, partiallysaturated, or fully unsaturated, said heterocyclic ring beingsubstituted with 0-2 R⁷,

C₁-C₄ alkoxy substituted with 0-2 R⁷,

hydroxy, CO₂H, nitro, —N(R¹⁰)R¹¹, —N(R¹⁶)R¹⁷, phenyl(C₀-C₄alkyl)carbonyl, phenyl(C₁-C₄ alkyl)-, heteroaryl(C₁-C₆ alkyl)-,CONR^(18a)R²⁰, SO₂R^(18a), and SO₂NR^(18a)R²⁰,

providing that any of the above alkyl, cycloalkyl, phenyl or heteroarylgroups may be unsubstituted or substituted independently with 1-2 R⁷;

R¹⁰ is selected from:

H, CF₃, C₃-C₆ alkenyl, C₃-C₁₁ cycloalkyl, phenyl,

(C₃-C₁₁ cycloalkyl)methyl, phenyl(C₁-C₄ alkyl), and

C₁-C₁₀ alkyl substituted with 0-2 R⁶;

R¹¹ is selected from:

H, hydroxy, C₁-C₈ alkyl, C₃-C₆ alkenyl, C₃-C₁₁ cycloalkyl, (C₃-C₁₁cycloalkyl)methyl, C₁-C₆ alkoxy,

benzyloxy, aryl, heteroaryl, heteroaryl(C₁-C₄ alkyl)-,

aryl(C₁-C₄ alkyl), adamantylmethyl, and

C₁-C₁₀ alkyl substituted with 0-2 R⁴;

alternatively, when R¹⁰ and R¹¹ are both substituents on the samenitrogen atom (as in —NR¹⁰R¹¹) they may be taken together with thenitrogen atom to which they are attached to form a heterocycle selectedfrom:

3-azabicyclononyl, 1,2,3,4-tetrahydro-1-quinolinyl,1,2,3,4-tetrahydro-2-isoquinolinyl, 1-piperidinyl, 1-morpholinyl,1-pyrrolidinyl, thiamorpholinyl, thiazolidinyl, and 1-piperazinyl;

said heterocycle being substituted with 0-3 groups selected from: C₁-C₆alkyl, aryl, heteroaryl, aryl(C₁-C₄ alkyl)-, (C₁-C₆ alkyl)carbonyl,(C₃-C₇ cycloalkyl)carbonyl, (C₁-C₆ alkoxy)carbonyl, aryl(C₁-C₄alkoxy)carbonyl, C₁-C₆ alkylsulfonyl, and arylsulfonyl;

R¹² is selected from:

H, C₁-C₆ alkyl, triphenylmethyl, methoxymethyl,

methoxyphenyldiphenylmethyl,

trimethylsilylethoxymethyl, (C₁-C₆ alkyl)carbonyl,

(C₁-C₆ alkoxy)carbonyl, (C₁-C₆ alkyl)aminocarbonyl,

C₃-C₆ alkenyl, C₃-C₇ cycloalkyl, C₃-C₇ cycloalkyl(C₁-C₄ alkyl)-, aryl,heteroaryl(C₁-C₆ alkyl)carbonyl,

heteroarylcarbonyl, aryl(C₁-C₆ alkyl)-,

(C₁-C₆ alkyl)carbonyl, arylcarbonyl, C₁-C₆

alkylsulfonyl, arylsulfonyl, aryl(C₁-C₆ alkyl)sulfonyl,

heteroarylsulfonyl, heteroaryl(C₁-C₆ alkyl)sulfonyl,

aryloxycarbonyl, and aryl(C₁-C₆ alkoxy)carbonyl,

wherein said aryl groups are substituted with 0-2 substituents selectedfrom the group consisting of C₁-C₄ alkyl, C₁-C₄ alkoxy, halo, CF₃, andnitro;

R¹⁴ is selected from H, CH₃, benzyl and phenylethyl;

R¹⁶ is selected from:

—C(═O)OR^(18a), —C(═O)R^(18b), —C(═O)N(R^(18b))₂, —C(═O)NHSO₂R^(18a),

—C(═O)NHC(═O)R^(18b), —C(═O)NHC(═O)OR^(18a),

—C(═O)NHSO₂NHR^(18b), —SO₂R^(18a), —SO₂N(R^(18b))₂, and

—SO₂NHC(═O)OR^(18b);

R¹⁷ is selected from:

H, C₁-C₆ alkyl, C₃-C₇ cycloalkyl, C₃-C₇ cycloalkyl(C₁-C₄ alkyl)-, aryl,aryl(C_(l)-C₆ alkyl)-, and heteroaryl(C₁-C₆ alkyl);

R^(18a) is selected from:

C₁-C₆ alkyl, aryl-, fluoro(C₃-C₆ alkyl), aryl(C₁-C₄ alkyl-, di(C₁-C₄alkyl)amino(C₁-C₄ alkyl),

morpholino(C₁-C₄ alkyl), piperidino(C₁-C₄ alkyl), N—(C₁-C₄alkyl)piperidino(C₁-C₄ alkyl), and phenyl substituted by one or twooptional groups selected from C₁-C₄ alkyl, C_(l)-C₄ alkoxy, and halogen;

R^(18b) is H or R^(18a);

R¹⁹ is selected from:

H, halogen, CF₃, CO₂H, CN, NO₂, —NR¹¹R¹², OCF₃,

C₁-C₈ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl,

C₃-C₁₁ cycloalkyl, C₃-C₇ cycloalkyl(C₁-C₄ alkyl)-,

aryl(C₁-C₆ alkyl)-, C₁-C₆ alkoxy, C₁-C₄ alkoxycarbonyl,

aryl, aryl-O—, aryl-SO2—, heteroaryl, and

heteroaryl-SO₂—, wherein said aryl and heteroaryl groups are substitutedwith 0-4 groups selected from hydrogen, halogen, CF₃, C₁-C₃ alkyl, andC₁-C₃ alkoxy;

R²⁰ is selected from:

hydroxy, C₁-C₁₀ alkyloxy, C₃-C₁₁ cycloalkyloxy,

aryloxy, aryl(C₁-C₄ alkyl)oxy,

C₂-C₁₀ alkylcarbonyloxy(C₁-C₂ alkyl)oxy-,

C₂-C₁₀ alkoxycarbonyloxy(C₁-C₂ alkyl)oxy-,

C₂-C₁₀ alkoxycarbonyl(C₁-C₂ alkyl)oxy-,

C₃-C₁₀ cycloalkylcarbonyloxy(C₁-C₂ alkyl)oxy-,

C₃-C₁₀ cycloalkoxycarbonyloxy(C₁-C₂ alkyl)oxy-,

C₃-C₁₀ cycloalkoxycarbonyl(C₁-C₂ alkyl)oxy-,

aryloxycarbonyl(C₁-C₂ alkyl)oxy-,

aryloxycarbonyloxy(C₁-C₂ alkyl)oxy-,

arylcarbonyloxy(C₁-C₂ alkyl)oxy-,

C₁-C₅ alkoxy(C₁-C₅ alkyl)carbonyloxy(C₁-C₂ alkyl)oxy-,

(5-(C₁-C₅ alkyl)-1,3-dioxa-cyclopenten-2-one-yl)methyloxy,

(5-aryl-1,3-dioxa-cyclopenten-2-one-yl)methyloxy, and

(R¹⁰)(R¹¹)N—(C₁-C₁₀ alkoxy)-;

R²¹ is selected from:

C₁-C₈ alkyl, C₂-C₆ alkenyl, C₃-C₁₁ cycloalkyl, (C₃-C₁₁cycloalkyl)methyl, aryl, aryl(C₁-C₄ alkyl)-, and C₁-C₁₀ alkylsubstituted with 0-2 R⁷;

m is 0-2;

n is 0-4;

p is 0-2; and

r is 0-2;

with the following provisos:

(1) n and m are chosen such that the number of atoms connecting R¹ andCOR²⁰ of Formula (III) is in the range of 8-14; and

(2) one of the groups R⁸ or R⁹ must be hydrogen.

[4c] More preferred compounds of the fourth embodiment of the presentinvention are those of Formula III:

including stereoisomeric forms thereof, or mixtures of stereoisomericforms thereof, or pharmaceutically acceptable salt or prodrug formsthereof wherein:

R¹ is selected from:

A is —CH₂— or —N(R¹²)—;

A¹ and B are independently —CH₂— or —N(R¹⁰)—;

D is —N(R¹²)— or —S—;

E-F is —C(R²)═C(R³)— or —C(R²)₂C(R³)₂—;

R² and R³ are independently selected from:

H, C₁-C₄ alkoxy, NR¹¹R¹², halogen, NO₂, CN, CF₃, C₁-C₆ alkyl, C₃-C₆alkenyl, C₃-C₇ cycloalkyl,

C₃-C₇ cycloalkyl(C₁-C₄ alkyl), aryl(C₁-C₆ akyl)-,

(C₁-C₆ alkyl)carbonyl, (C₁-C₆ alkoxy)carbonyl,

arylcarbonyl, and aryl substituted with 0-4 R⁷,

alternatively, when R² and R³ are substituents on adjacent atoms, theycan be taken together with the carbon atoms to which they are attachedto form a 5-7 membered carbocyclic or 5-7 membered heterocyclic aromaticor nonaromatic ring system, said carbocyclic or heterocyclic ring beingsubstituted with 0-2 groups selected from C₁-C₄ alkyl, C₁-C₄ alkoxy,halo, cyano, amino, CF₃ and NO₂;

R⁴ is selected from:

H, C₁-C₆ alkyl, C₃-C₇ cycloalkyl, C₃-C₇ cycloalkyl(C₁-C₄ alkyl)-, aryl,heteroaryl, aryl(C₁-C₆ alkyl)-, and

heteroaryl(C₁-C₆ alkyl)-, wherein said aryl or heteroaryl groups aresubstituted with 0-2 substituents independently selected from the groupconsisting of C₁-C₄ alkyl, C₁-C₄ alkoxy, F, Cl, Br, CF₃, and NO₂,

R⁶ is selected from:

H, C₁-C₁₀ alkyl, hydroxy, C₁-C₁₀ alkoxy, nitro, C₁-C₁₀ alkylcarbonyl,—N(R¹¹)R¹², cyano, halo, CF₃, CHO, CO₂R^(18b), C(═O)R^(18b),CONR¹⁷R^(18b), OC(═O)R¹⁰, OR¹⁰, OC(═O)NR¹⁰R¹¹, NR¹⁰C(═O)R¹⁰,NR¹⁰C(═O)OR²¹, NR¹⁰C(═O) NR¹⁰R¹¹, NR¹⁰SO₂NR¹⁰R¹¹, NR¹⁰SO₂R²¹,S(O)_(p)R¹¹, SO₂NR¹⁰R¹¹,

aryl substituted with 0-3 groups selected from halogen, C₁-C₆ alkoxy,C₁-C₆ alkyl, CF₃, S(O)_(m)Me, and —NMe₂,

aryl(C₁-C₄ alkyl)-, said aryl being substituted with 0-3 groups selectedfrom halogen, C₁-C₆ alkoxy, C₁-C₆ alkyl, CF₃, S(O)_(p)Me, and —NMe₂, and

a 5-10 membered heterocyclic ring containing 1-3 N, O, or S heteroatoms,wherein said heterocyclic ring may be saturated, partially saturated, orfully unsaturated, said heterocyclic ring being substituted with 0-2 R⁷;

R⁷ is selected from:

H, hydroxy, C₁-C₄ alkyl, C₁-C₄ alkoxy, aryl, aryl(C₁-C₄ alkyl)-, (C₁-C₄alkyl)carbonyl, CO₂R^(18a), SO₂R¹¹,

SO₂NR¹⁰R¹¹, OR¹⁰, and N(R¹¹)R¹²;

U is selected from:

—(CH₂)_(n)—, —NH(CH₂)_(n)—, —N(R¹⁰)C(═O)—, and —NHC(═O)(CH₂)_(n)—;

G is N or CR¹⁹;

R⁸ is H;

R⁹ is selected from:

H, hydroxy, CO₂H, nitro, —N(R¹⁰)R¹¹, —N(R¹⁶)R¹⁷, phenyl(C₀-C₄alkyl)carbonyl, phenyl(C₁-C₄ alkyl)-, heteroaryl(C₁-C₆ alkyl)-,CONR^(18a)R²⁰, SO₂R^(18a), and SO₂NR^(18a)R²⁰,

providing that any of the above phenyl or heteroaryl groups may beunsubstituted or substituted independently with 1-2 R⁷;

R¹⁰ is selected from:

H, CF₃, C₃-C₆ alkenyl, C₃-C₁₁ cycloalkyl, phenyl,

(C₃-C₁₁ cycloalkyl)methyl, phenyl(C₁-C₄ alkyl), and

C₁-C₁₀ alkyl substituted with 0-2 R⁶;

R¹¹ is selected from:

H, hydroxy, C₁-C₈ alkyl, C₃-C₆ alkenyl, C₃-C₁₁ cycloalkyl, (C₃-C₁₁cycloalkyl)methyl, C₁-C₆ alkoxy,

benzyloxy, aryl, heteroaryl, heteroaryl(C₁-C₄ alkyl)-,

aryl(C₁-C₄ alkyl), adamantylmethyl, and

C₁-C₁₀ alkyl substituted with 0-2 R⁴;

alternatively, when R¹⁰ and R¹¹ are both substituents on the samenitrogen atom (as in —NR¹⁰R¹¹) they may be taken together with thenitrogen atom to which they are attached to form a heterocycle selectedfrom:

3-azabicyclononyl, 1,2,3,4-tetrahydro-1-quinolinyl,1,2,3,4-tetrahydro-2-isoquinolinyl, 1-piperidinyl, 1-morpholinyl,1-pyrrolidinyl, thiamorpholinyl, thiazolidinyl, and 1-piperazinyl;

said heterocycle being substituted with 0-3 groups selected from: C₁-C₆alkyl, aryl, heteroaryl, aryl(C₁-C₄ alkyl)-, (C₁-C₆ alkyl)carbonyl,(C₃-C₇ cycloalkyl)carbonyl, (C₁-C₆ alkoxy)carbonyl, aryl(C₁-C₄alkoxy)carbonyl, C₁-C₆ alkylsulfonyl, and arylsulfonyl;

R¹² is selected from:

H, C₁-C₄ alkyl, (C₁-C₄ alkyl)carbonyl, (C₁-C₄ alkoxy)carbonyl,phenyl(C₁-C₄ alkyl)-, phenylsulfonyl,

phenyloxycarbonyl, and phenyl(C₁-C₄ alkoxy)carbonyl,

wherein said phenyl groups are substituted with 0-2 substituentsselected from the group consisting of C₁-C₄ alkyl, C₁-C₄ alkoxy, halo,CF₃, and nitro;

R¹⁴ is selected from H, CF₃, CH₃, and benzyl;

R¹⁶ is selected from:

—C(═O)OR^(18a), —C(═O)R^(18b), —C(═O)N(R^(18b))₂, —C(═O)NHSO₂R^(18a),

—C(═O)NHC(═O)R^(18b), —C(═O)NHC(═O)OR^(18a),

—C(═O)NHSO₂NHR^(18b), —SO₂R^(18a), —SO₂N(R^(18b))₂, and

—SO₂NHC(═O)OR^(18b);

R¹⁷ is selected from:

H, C₁-C₆ alkyl, C₃-C₇ cycloalkyl, C₃-C₇ cycloalkyl(C₁-C₄ alkyl)-, aryl,aryl(C₁-C₆ alkyl)-, and heteroaryl(C₁-C₆ alkyl);

R^(18a) is selected from:

C₁-C₆ alkyl, aryl-, fluoro (C₃-C₆ alkyl), aryl(C₁-C₄ alkyl-, di(C₁-C₄alkyl)amino(C₁-C₄ alkyl),

morpholino(C₁-C₄ alkyl), piperidino(C₁-C₄ alkyl), N—(C₁-C₄alkyl)piperidino(C₁-C₄ alkyl), and phenyl substituted by one or twooptional groups selected from C₁-C₄ alkyl, C₁-C₄ alkoxy, and halogen;

R^(18b) is H or R^(18a);

R¹⁹ is selected from:

H, halogen, CF₃, CO₂H, CN, NO₂, —NR¹¹R¹², OCF₃,

C₁-C₈ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl,

C₃-C₁₁ cycloalkyl, C₃-C₇ cycloalkyl(C₁-C₄ alkyl)-,

aryl(C₁-C₆ alkyl)-, C₁-C₆ alkoxy, C₁-C₄ alkoxycarbonyl,

aryl, aryl-O—, aryl-SO₂—, heteroaryl, and

heteroaryl-SO₂—, wherein said aryl and heteroaryl groups are substitutedwith 0-4 groups selected from hydrogen, halogen, CF₃, C₁-C₃ alkyl, andC₁-C₃ alkoxy;

R²⁰ is selected from:

hydroxy, C₁-C₁₀ alkyloxy, C₃-C₁₁ cycloalkyloxy,

aryloxy, aryl(C₁-C₄ alkyl)oxy,

C₂-C₁₀ alkylcarbonyloxy(C₁-C₂ alkyl)oxy-,

C₂-C₁₀ alkoxycarbonyloxy(C₁-C₂ alkyl)oxy-,

C₂-C₁₀ alkoxycarbonyl(C₁-C₂ alkyl)oxy-,

C₃-C₁₀ cycloalkylcarbonyloxy(C₁-C₂ alkyl)oxy-,

C₃-C₁₀ cycloalkoxycarbonyloxy(C₁-C₂ alkyl)oxy-,

C₃-C₁₀ cycloalkoxycarbonyl(C₁-C₂ alkyl)oxy-,

aryloxycarbonyl(C₁-C₂ alkyl)oxy-,

aryloxycarbonyloxy( C₁-C₂ alkyl)oxy-,

arylcarbonyloxy(C₁-C₂ alkyl)oxy-,

C₁-C₅ alkoxy(C₁-C₅ alkyl)carbonyloxy(C₁-C₂ alkyl)oxy-,

(5-(C₁-C₅ alkyl)-1,3-dioxa-cyclopenten-2-one-yl)methyloxy,

(5-aryl-1,3-dioxa-cyclopenten-2-one-yl)methyloxy, and

(R¹⁰)(R¹¹)N—(C₁-C₁₀ alkoxy)-;

R²¹ is selected from:

C₁-C₈ alkyl, C₂-C₆ alkenyl, C₃-C₁₁ cycloalkyl, (C₃-C₁₁cycloalkyl)methyl, aryl, aryl(C₁-C₄ alkyl)-, and C₁-C₁₀ alkylsubstituted with 0-2 R⁷;

m is 0-2;

n is 0-4;

p is 0-2; and

r is 0-2;

with the following provisos:

1) n and m are chosen such that the number of atoms connecting R¹ andCOR²⁰ of Formula (III) is in the range of 8-14; and

(2) one of the groups R⁸ or R⁹ must be hydrogen.

[4d] Further preferred compounds of the fourth embodiment of the presentinvention are those of Formula III:

including stereoisomeric forms thereof, or mixtures of stereoisomericforms thereof, or pharmaceutically acceptable salt or prodrug formsthereof wherein:

R¹ is selected from:

R⁴ is selected from:

H, C₁-C₆ alkyl, C₃-C₇ cycloalkyl, C₃-C₇ cycloalkyl(C₁-C₄ alkyl)-, aryl,heteroaryl, aryl(C₁-C₆ alkyl)-, and

heteroaryl(C₁-C₆ alkyl)-, wherein said aryl or heteroaryl groups aresubstituted with 0-2 substituents independently selected from the groupconsisting of C₁-C₄ alkyl, C₁-C₄ alkoxy, F, Cl, Br, CF₃, and NO₂,

R⁶ is selected from:

H, C₁-C₁₀ alkyl, hydroxy, C₁-C₁₀ alkoxy, nitro, C₁-C₁₀ alkylcarbonyl,—N(R¹¹)R¹², cyano, halo, CF₃, CHO, CO₂R^(18b), C(═O)R^(18b),CONR¹⁷R^(18b), OC(═O)R¹⁰, OR¹⁰, OC(═O)NR¹⁰R¹¹, NR¹⁰C(═O)R¹⁰,NR¹⁰C(═O)OR²¹, NR¹⁰C(═O)NR¹⁰R¹¹, NR¹⁰SO₂NR¹⁰R¹¹, NR¹⁰SO₂R²¹,S(O)_(p)R¹¹, SO₂NR¹⁰R¹¹,

aryl substituted with 0-3 groups selected from halogen, C₁-C₆ alkoxy,C₁-C₆ alkyl, CF₃, S(O)_(m)Me, and —NMe₂,

aryl(C₁-C₄ alkyl)-, said aryl being substituted with 0-3 groups selectedfrom halogen, C₁-C₆ alkoxy, C₁-C₆ alkyl, CF₃, S(O)_(p)Me, and —NMe₂, and

a 5-10 membered heterocyclic ring containing 1-3 N, O, or S heteroatoms,wherein said heterocyclic ring may be saturated, partially saturated, orfully unsaturated, said heterocyclic ring being substituted with 0-2 R⁷;

R⁷ is selected from:

H, hydroxy, C₁-C₄ alkyl, C₁-C₄ alkoxy, aryl, aryl(C₁-C₄ alkyl)-, (C₁-C₄alkyl)carbonyl, CO₂R^(18a), SO₂R¹¹,

SO₂NR¹⁰R¹¹, OR¹⁰, and N(R¹¹)R¹²;

U is selected from:

—(CH₂)_(n)—, —NH(CH₂)_(n)—, —N(R¹⁰)C(═O)—, and —NHC(═O)(CH₂)_(n)—;

G is N or CR¹⁹;

R⁸ is H;

R⁹ is selected from:

H, hydroxy, CO₂H, —N(R¹⁰)R¹¹, —N(R¹⁶)R¹⁷, phenyl(C₀-C₄ alkyl)carbonyl,phenyl(C₁-C₄ alkyl)-, heteroaryl(C₁-C₆ alkyl)-, CONR^(18a)R²⁰,SO₂R^(18a), and SO₂NR^(18a)R²⁰,

providing that any of the above phenyl or heteroaryl groups may beunsubstituted or substituted independently with 1-2 R⁷;

R¹⁰ is selected from:

H, CF₃, C₃-C₆ alkenyl, C₃-C₁₁ cycloalkyl, phenyl, (C₃-C₁₁cycloalkyl)methyl, phenyl(C₁-C₄ alkyl), and C₁-C₁₀ alkyl substitutedwith 0-2 R⁶;

R¹¹ is selected from:

H, hydroxy, C₁-C₈ alkyl, C₃-C₆ alkenyl, C₃-C₁₁ cycloalkyl, (C₃-C₁₁cycloalkyl)methyl, C₁-C₆ alkoxy, benzyloxy, aryl, heteroaryl,heteroaryl(C₁-C₄ alkyl)-, aryl(C₁-C₄ alkyl), adamantylmethyl, and C₁-C₁₀alkyl substituted with 0-2 R⁴;

alternatively, when R¹⁰ and R¹¹ are both substituents on the samenitrogen atom (as in —NR¹⁰R¹¹) they may be taken together with thenitrogen atom to which they are attached to form a heterocycle selectedfrom:

3-azabicyclononyl, 1,2,3,4-tetrahydro-1-quinolinyl,1,2,3,4-tetrahydro-2-isoquinolinyl, 1-piperidinyl, 1-morpholinyl,1-pyrrolidinyl, thiamorpholinyl, thiazolidinyl, and 1-piperazinyl;

said heterocycle being substituted with 0-3 groups selected from: C₁-C₆alkyl, aryl, heteroaryl, aryl (C₁-C₄ alkyl)-, (C₁-C₆ alkyl)carbonyl,(C₃-C₇ cycloalkyl)carbonyl, (C₁-C₆ alkoxy)carbonyl, aryl(C₁-C₄alkoxy)carbonyl, C₁-C₆ alkylsulfonyl, and arylsulfonyl;

R¹² is selected from:

H, C₁-C₄ alkyl, (C₁-C₄ alkyl)carbonyl, (C₁-C₄ alkoxy)carbonyl,phenyl(C₁-C₄ alkyl)-, phenylsulfonyl, phenyloxycarbonyl, andphenyl(C₁-C₄ alkoxy)carbonyl, wherein said phenyl groups are substitutedwith 0-2 substituents selected from the group consisting of C₁-C₄ alkyl,C₁-C₄ alkoxy, halo, CF₃, and nitro;

R¹⁴ is selected from H, CF₃, CH₃, and benzyl;

R¹⁶ is selected from:

—C(═O)OR^(18a), —C(═O)R^(18b), —C(═O)N(R^(18b))₂, —C(═O)NHSO₂R^(18a),—C(═O)NHC(═O)R^(18b), —C(═O)NHC(═O)OR^(18a), —C(═O)NHSO₂NHR^(18b),—SO₂R^(18a), —SO₂N(R^(18b))₂, and —SO₂NHC(═O)OR^(18b);

R¹⁷ is selected from:

H, C₁-C₆ alkyl, C₃-C₇ cycloalkyl, C₃-C₇ cycloalkyl(C₁-C₄ alkyl)-, aryl,aryl(C₁-C₆ alkyl)-, and heteroaryl(C₁-C₆ alkyl);

R^(18a) is selected from:

C₁-C₆ alkyl, aryl-, fluoro(C₃-C₆ alkyl), aryl(C₁-C₄ alkyl-, di(C₁-C₄alkyl)amino(C₁-C₄ alkyl), morpholino(C₁-C₄ alkyl), piperidino(C₁-C₄alkyl), N—(C₁-C₄ alkyl)piperidino(C₁-C₄ alkyl), and phenyl substitutedby one or two optional groups selected from C₁-C₄ alkyl, C₁-C₄ alkoxy,and halogen;

R^(18b) is H or R^(18a);

R¹⁹ is selected from:

H, halogen, CF₃, CO₂H, CN, NO₂, —NR¹¹R¹², OCF₃,

C₁-C₈ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl,

C₃-C₁₁ cycloalkyl, C₃-C₇ cycloalkyl(C₁-C₄ alkyl)-,

aryl(C₁-C₆ alkyl)-, C₁-C₆ alkoxy, C₁-C₄ alkoxycarbonyl,

aryl, aryl-O—, aryl-SO₂—, heteroaryl, and

heteroaryl-SO₂-, wherein said aryl and heteroaryl groups are substitutedwith 0-4 groups selected from hydrogen, halogen, CF₃, C₁-C₃ alkyl, andC₁-C₃ alkoxy;

R²⁰ is selected from:

hydroxy, C₁-C₁₀ alkyloxy, C₃-C₁₁ cycloalkyloxy,

aryloxy, aryl(C₁-C₄ alkyl)oxy,

C₂-C₁₀ alkylcarbonyloxy(C₁-C₂ alkyl)oxy-,

C₂-C₁₀ alkoxycarbonyloxy(C₁-C₂ alkyl)oxy-,

C₂-C₁₀ alkoxycarbonyl(C₁-C₂ alkyl)oxy-,

C₃-C₁₀ cycloalkylcarbonyloxy(C₁-C₂ alkyl)oxy-,

C₃-C₁₀ cycloalkoxycarbonyloxy(C₁-C₂ alkyl)oxy-,

C₃-C₁₀ cycloalkoxycarbonyl(C₁-C₂ alkyl)oxy-,

aryloxycarbonyl(C₁-C₂ alkyl)oxy-,

aryloxycarbonyloxy(C₁-C₂ alkyl)oxy-,

arylcarbonyloxy(C₁-C₂ alkyl)oxy-,

C₁-C₅ alkoxy(C₁-C₅ alkyl)carbonyloxy(C₁-C₂ alkyl)oxy-,

(5-(C₁-C₅ alkyl)-1,3-dioxa-cyclopenten-2-one-yl)methyloxy,

(5-aryl-1,3-dioxa-cyclopenten-2-one-yl)methyloxy, and

(R¹⁰)(R¹¹)N—(C₁-C₁₀ alkoxy)-;

R²¹ is selected from:

C₁-C₈ alkyl, C₂-C₆ alkenyl, C₃-C₁₁ cycloalkyl, (C₃-C₁₁cycloalkyl)methyl, aryl, aryl(C₁-C₄ alkyl)-, and C₁-C₁₀ alkylsubstituted with 0-2 R⁷;

m is 0-2;

n is 0-4;

p is 0-2; and

r is 0-2;

with the following provisos:

(1) n and m are chosen such that the number of atoms connecting R¹ andCOR²⁰ in Formula (III) is in the range of 8-14; and

(2) one of the groups R⁸ or R⁹ must be hydrogen.

[4e] Specifically preferred compounds of the above invention arecompounds of Formula III including enantiomeric or diastereomeric formsthereof, or mixtures of enantiomeric or diastereomeric forms thereof, orpharmaceutically acceptable salt or prodrug forms thereof selected fromthe group consisting of:

3-[7-[(imidazol-2-ylamino)methyl]-1-cyclopropylylquinoline-4-one-3-ylcarbonylamino]-2-((2,4,6-trimethylphenyl)sulfonylamino)propionicacid,

3-[7-[(imidazol-2-ylamino)methyl]-1-cyclopentylquinoline-4-one-3-ylcarbonylamino]-2-((4-phenylbenzene)sulfonylamino)propionicacid,

3-[7-[(benzimidazol-2-ylamino)methyl]-1-methylquinoline-4-one-3-ylcarbonylamino]-2-((2,4,6-trimethylphenyl)sulfonylamino)propionicacid,

3-[7-[(4,5-dimethylimidazol-2-ylamino)methyl]-1-trifluoromethylquinoline-4-one-3-ylcarbonylamino]-2-((2,6-dichlorophenyl)sulfonylamino)propionicacid,

3-[7-(2-aminopyridin-6-yl)-1-phenylquinoline-4-one-3-ylcarbonylamino]-2-((2,4,6-trimethylphenyl)sulfonylamino)propionic acid,

3-[7-[(7-azabenzimidazol-2-yl)methyl]-1-cyclohexylquinoline-4-one-3-ylcarbonylamino]-2-((2,4,6-trimethylphenyl)sulfonylamino)propionicacid,

3-[7-[(imidazol-2-ylamino)methyl]-1-cyclopropylquinoline-4-one-3-ylcarbon-ylamino]-2-((2,2-dichloro-4-phenylbenzene)sulfonylamino)propionic acid,

In a fifth embodiment the present invention provides for a method forthe treatment of cancer metastasis, diabetic retinopathy, neovascularglaucoma, thrombosis, restenosis, osteoporosis, or macular degenerationwhich comprises administering to a host in need of such treatment atherapeutically effective amount of a compound of Formula (I) or Formula(II).

In a sixth embodiment the present invention provides for apharmaceutical composition comprising a pharmaceutically acceptablecarrier and a compound of Formula (I) or Formula (II).

In the present invention it has been discovered that the compounds ofFormulae I-IV above are useful as inhibitors of cell-matrix andcell-cell adhesion processes. The present invention includes novelcompounds of Formulae I-IV and methods for using such compounds for theprevention or treatment of diseases resulting from abnormal celladhesion to the extracellular matrix which comprises administering to ahost in need of such treatment a therapeutically effective amount ofsuch compound of Formulae I-IV.

In the present invention it has also been discovered that the compoundsof Formulae I-IV above are useful as inhibitors of α_(v)β₃. Thecompounds of the present invention inhibit the binding of vitronectin toα_(v)β₃ and inhibit cell adhesion.

The present invention also provides pharmaceutical compositionscomprising a compound of Formulae I-IV and a pharmaceutically acceptablecarrier.

The compounds of Formulae I-IV of the present invention are useful forthe treatment (including prevention) of angiogenic disorders. The term“angiogenic disorders” as used herein includes conditions involvingabnormal neovascularization, such as tumor metastasis and ocularneovascularization, including, for example, diabetic retinopathy,neovascular glaucoma, age-related macular degeneration, and retinal veinocclusion, comprising administering to a mammal in need of suchtreatment a therapeutically effective amount of a compound of FormulaeI-IV described above.

The compounds of Formulae I-IV of the present invention may be usefulfor the treatment or prevention of other diseases which involve celladhesion processes, including, but not limited to, inflammation, bonedegradation, thromboembolic disorders, restenosis, rheumatoid arthritis,asthma, allergies, adult respiratory distress syndrome, graft versushost disease, organ transplantation rejection, septic shock, psoriasis,eczema, contact dermatitis, osteoporosis, osteoarthritis,atherosclerosis, inflammatory bowel disease and other autoimmunediseases. The compounds of Formulae IV of the present invention may alsobe useful for wound healing.

The term “thromboembolic disorders” as used herein includes conditionsinvolving platelet activation and aggregation, such as arterial orvenous cardiovascular or cerebrovascular thromboembolic disorders,including, for example, thrombosis, unstable angina, first or recurrentmyocardial infarction, ischemic sudden death, transient ischemic attack,stroke, atherosclerosis, venous thrombosis, deep vein thrombosis,thrombophlebitis, arterial embolism, coronary and cerebral arterialthrombosis, myocardial infarction, cerebral embolism, kidney embolisms,pulmonary embolisms, or such disorders associated with diabetes,comprising administering to a mammal in need of such treatment atherapeutically effective amount of a compound of Formulae I-IVdescribed above.

The compounds of the present invention may be used for other ex vivoapplications to prevent cellular adhesion in biological samples.

The compounds of the present invention can also be administered incombination with one or more additional therapeutic agents selectedfrom: anti-coagulant or coagulation inhibitory agents, such as heparinor warfarin; anti-platelet or platelet inhibitory agents, such asaspirin, piroxicam, ticlopidine, or clopidogrel; factor Xa inhibitors;thrombin inhibitors such as boropeptides, hirudin or argatroban; orthrombolytic or fibrinolytic agents, such as plasminogen activators,anistreplase, urokinase, or streptokinase.

The compounds of Formulae I-IV of the present invention can beadministered in combination with one or more of the foregoing additionaltherapeutic agents, thereby to reduce the doses of each drug required toachieve the desired therapeutic effect. Thus, the combination treatmentof the present invention permits the use of lower doses of eachcomponent, with reduced adverse, toxic effects of each component. Alower dosage minimizes the potential of side effects of the compounds,thereby providing an increased margin of safety relative to the marginof safety for each component when used as a single agent. Suchcombination therapies may be employed to achieve synergistic or additivetherapeutic effects for the treatment of thromboembolic disorders.

By “therapeutically effective amount” it is meant an amount of acompound of Formulae I-IV that when administered alone or in combinationwith an additional therapeutic agent to a cell or mammal is effective toprevent or ameliorate the thromboembolic disease condition or theprogression of the disease.

By “administered in combination” or “combination therapy” it is meantthat the compound of Formulae I-IV and one or more additionaltherapeutic agents are administered concurrently to the mammal beingtreated. When administered in combination each component may beadministered at the same time or sequentially in any order at differentpoints in time. Thus, each component may be administered separately butsufficiently closely in time so as to provide the desired therapeuticeffect. The term anti-coagulant agents (or coagulation inhibitoryagents), as used herein, denotes agents that inhibit blood coagulation.Such agents include warfarin (available as COUMADIN™) and heparin.

The term anti-platelet agents (or platelet inhibitory agents), as usedherein, denotes agents that inhibit platelet function such as byinhibiting the aggregation, adhesion or granular secretion of platelets.Such agents include the various known non-steroidal anti-inflammatorydrugs (NSAIDS) such as aspirin, ibuprofen, naproxen, sulindac,indomethacin, mefenamate, droxicam, diclofenac, sulfinpyrazone, andpiroxicam, including pharmaceutically acceptable salts or prodrugsthereof. Of the NSAIDS, aspirin (acetylsalicyclic acid or ASA), andpiroxicam. Piroxicam is commercially available from Pfizer, Inc. (NewYork, N.Y.), as Feldane®. Other suitable anti-platelet agents includeticlopidine and clopidogrel, including pharmaceutically acceptable saltsor prodrugs thereof. Ticlopidine and clopidogrel are also preferredcompounds since they are known to be gentle on the gastro-intestinaltract in use. Still other suitable platelet inhibitory agents includethromboxane-A2-receptor antagonists and thromboxane-A2-synthetaseinhibitors, as well as pharmaceutically acceptable salts or prodrugsthereof.

The phrase thrombin inhibitors (or anti-thrombin agents), as usedherein, denotes inhibitors of the serine protease thrombin. Byinhibiting thrombin, various thrombin-mediated processes, such asthrombin-mediated platelet activation (that is, for example, theaggregation of platelets, and/or the granular secretion of plasminogenactivator inhibitor-1 and/or serotonin) and/or fibrin formation aredisrupted. Such inhibitors include boroarginine derivatives andboropeptides, hirudin and argatroban, including pharmaceuticallyacceptable salts and prodrugs thereof. Boroarginine derivatives andboropeptides include N-acetyl and peptide derivatives of boronic acid,such as C-terminal α-aminoboronic acid derivatives of lysine, ornithine,arginine, homoarginine and corresponding isothiouronium analogs thereof.The term hirudin, as used herein, includes suitable derivatives oranalogs of hirudin, referred to herein as hirulogs, such asdisulfatohirudin. Boropeptide thrombin inhibitors include compoundsdescribed in Kettner et al., U.S. Pat. No. 5,187,157 and European PatentApplication Publication Number 293 881 A2, the disclosures of which arehereby incorporated herein by reference. Other suitable boroargininederivatives and boropeptide thrombin inhibitors include those disclosedin PCT Application Publication Number 92/07869 and European PatentApplication Publication Number 471 651 A2, the disclosures of which arehereby incorporated herein by reference, in their entirety.

The phrase thrombolytics (or fibrinolytic) agents (or thrombolytics orfibrinolytics), as used herein, denotes agents that lyse blood clots(thrombi). Such agents include tissue plasminogen activator,anistreplase, urokinase or streptokinase, including pharmaceuticallyacceptable salts or prodrugs thereof. Tissue plasminogen activator (tPA)is commercially available from Genentech Inc., South San Francisco,Calif. The term anistreplase, as used herein, refers to anisoylatedplasminogen streptokinase activator complex, as described, for example,in European Patent Application No. 028,489, the disclosures of which arehereby incorporated herein by reference herein, in their entirety.Anistreplase is commercially available as Eminase®. The term urokinase,as used herein, is intended to denote both dual and single chainurokinase, the latter also being referred to herein as pro-urokinase.

Administration of the compounds of Formulae I-IV of the invention incombination with such additional therapeutic agent, may afford anefficacy advantage over the compounds and agents alone, and may do sowhile permitting the use of lower doses of each. A lower dosageminimizes the potential of side effects, thereby providing an increasedmargin of safety.

The compounds of the present invention are also useful as standard orreference compounds, for example as a quality standard or control, intests or assays involving the binding of vitronectin or fibrinogen toα_(v)β₃. Such compounds may be provided in a commercial kit, forexample, for use in pharmaceutical research involving α_(v)β₃. Thecompounds of the present invention may also be used in diagnostic assaysinvolving α_(v)β₃.

The compounds herein described may have asymmetric centers. Unlessotherwise indicated, all chiral, diastereomeric and racemic forms areincluded in the present invention. Many geometric isomers of olefins,C═N double bonds, and the like can also be present in the compoundsdescribed herein, and all such stable isomers are contemplated in thepresent invention. It will be appreciated that compounds of the presentinvention that contain asymmetrically substituted carbon atoms may beisolated in optically active or racemic forms. It is well known in theart how to prepare optically active forms, such as by resolution ofracemic forms or by synthesis, from optically active starting materials.All chiral, diastereomeric, racemic forms and all geometric isomericforms of a structure are intended, unless the specific stereochemistryor isomer form is specifically indicated.

When any variable (for example but not limited to, R², R⁴, R⁶, R⁷,R⁸,R¹²,and R¹⁴, n, etc.) occurs more than one time in any constituent or inany formula, its definition on each occurrence is independent of itsdefinition at every other occurrence. Thus, for example, if a group isshown to be substituted with 0-2 R⁴, then said group may optionally besubstituted with up to two R⁴ and R⁴ at each occurrence is selectedindependently from the defined list of possible R⁴. Also, by way ofexample, for the group —N(R^(5a))₂, each of the two R^(5a) substituentson N is independently selected from the defined list of possible R^(5a).Similarly, by way of example, for the group —C(R⁷)₂—, each of the two R⁷substituents on C is independently selected from the defined list ofpossible R⁷.

When a bond to a substituent is shown to cross the bond connecting twoatoms in a ring, then such substituent may be bonded to any atom on thering. When a bond joining a substituent to another group is notspecifically shown or the atom in such other group to which the bondjoins is not specifically shown, then such substituent may form a bondwith any atom on such other group.

When a substituent is listed without indicating the atom via which suchsubstituent is bonded to the rest of the compound of Formulae I-IV, thensuch substituent may be bonded via any atom in such substituent. Forexample, when the substituent is piperazinyl, piperidinyl, ortetrazolyl, unless specified otherwise, said piperazinyl, piperidinyl,tetrazolyl group may be bonded to the rest of the compound of FormulaeI-IV via any atom in such piperazinyl, piperidinyl, tetrazolyl group.

Combinations of substituents and/or variables are permissible only ifsuch combinations result in stable compounds. By stable compound orstable structure it is meant herein a compound that is sufficientlyrobust to survive isolation to a useful degree of purity from a reactionmixture, and formulation into an efficacious therapeutic agent.

The term “substituted”, as used herein, means that any one or morehydrogen on the designated atom is replaced with a selection from theindicated group, provided that the designated atom's normal valency isnot exceeded, and that the substitution results in a stable compound.When a substituent is keto (i.e., ═O), then 2 hydrogens on the atom arereplaced.

As used herein, “alkyl” is intended to include both branched andstraight-chain saturated aliphatic hydrocarbon groups having thespecified number of carbon atoms (for example, “C₁-C₁₀” denotes alkylhaving 1 to 10 carbon atoms); “haloalkyl” is intended to include bothbranched and straight-chain saturated aliphatic hydrocarbon groupshaving the specified number of carbon atoms, substituted with 1 or morehalogen (for example —C_(v)F_(w) where v=1 to 3 and w=1 to (2v+1));“alkoxy” represents an alkyl group of indicated number of carbon atomsattached through an oxygen bridge; “cycloalkyl” is intended to includesaturated ring groups, including mono-, bi-, or polycyclic ring systems,such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,cyclooctyl, and adamantyl; and “biycloalkyl”, is intended to includesaturated bicyclic ring groups such as [3.3.0]bicyclooctane,[4.3.0]bicyclononane, [4.4.0]bicyclodecane (decalin),[2.2.2]bicyclooctane, and so forth. “Alkenyl” is intended to includehydrocarbon chains of either a straight or branched configuration andone or more unsaturated carbon-carbon bonds which may occur in anystable point along the chain, such as ethenyl, propenyl and the like;and “alkynyl” is intended to include hydrocarbon chains of either astraight or branched configuration and one or more triple carbon-carbonbonds which may occur in any stable point along the chain, such asethynyl, propynyl and the like.

The terms “alkylene”, “alkenylene”, “phenylene”, and the like, refer toalkyl, alkenyl, and phenyl groups, respectively, which are connected bytwo bonds to the rest of the structure of Formulae I-IV. Such“alkylene”, “alkenylene”, “phenylene”, and the like, may alternativelyand equivalently be denoted herein as “-(alkyl)-”, “-(alkenyl)-” and“-(phenyl)-”, and the like.

“Halo” or “halogen” as used herein refers to fluoro, chloro, bromo andiodo; and “counterion” is used to represent a small, negatively chargedspecies such as chloride, bromide, hydroxide, acetate, sulfate and thelike.

As used herein, “aryl” or “aromatic residue” is intended to mean phenylor naphthyl optionally substituted with 1-3 R¹⁹; the term “arylalkyl”represents an aryl group attached through an alkyl bridge.

As used herein, “carbocycle” or “carbocyclic residue” is intended tomean any stable 3- to 7-membered monocyclic or bicyclic or 7- to14-membered bicyclic or tricyclic or an up to 26-membered polycycliccarbon ring, any of which may be saturated, partially unsaturated, oraromatic. Examples of such carbocyles include, but are not limited to,cyclopropyl, cyclopentyl, cyclohexyl, phenyl, biphenyl, naphthyl,indanyl, adamantyl, or tetrahydronaphthyl (tetralin).

As used herein, the term “heterocycle” or “heterocyclic” is intended tomean a stable 5- to 7-membered monocyclic or bicyclic or 7- to10-membered bicyclic heterocyclic ring which may be saturated, partiallyunsaturated, or aromatic, and which consists of carbon atoms and from 1to 4 heteroatoms independently selected from the group consisting of N,O and S and wherein the nitrogen and sulfur heteroatoms may optionallybe oxidized, and the nitrogen may optionally be quaternized, andincluding any bicyclic group in which any of the above-definedheterocyclic rings is fused to a benzene ring. The heterocyclic ring maybe attached to its pendant group at any heteroatom or carbon atom whichresults in a stable structure. The heterocyclic rings described hereinmay be substituted on carbon or on a nitrogen atom if the resultingcompound is stable. Examples of such heterocycles include, but are notlimited to, pyridyl (pyridinyl), pyrimidinyl, furanyl (furyl),thiazolyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, tetrazolyl,benzofuranyl, benzothiophenyl, indolyl, indolenyl, isoxazolinyl,isoxazolyl, quinolinyl, isoquinolinyl, benzimidazolyl, piperidinyl,4-piperidonyl, pyrrolidinyl, 2-pyrrolidonyl, pyrrolinyl,tetrahydrofuranyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl,decahydroquinolinyl or octahydroisoquinolinyl, azocinyl, triazinyl,6H-1,2,5-thiadiazinyl, 2H,6H-1,5,2-dithiazinyl, thianthrenyl, pyranyl,isobenzofuranyl, chromenyl, xanthenyl, phenoxathiinyl, 2H-pyrrolyl,pyrrolyl, imidazolyl, pyrazolyl, isothiazolyl, isoxazolinyl, isoxazolyl,oxazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolizinyl,isoindolyl, 3H-indolyl, indolyl, 1H-indazolyl, purinyl, 4H-quinolizinyl,isoquinolinyl, quinolinyl, phthalazinyl, naphthyridinyl, quinoxalinyl,quinazolinyl, cinnolinyl, pteridinyl, 4aH-carbazole, carbazole,β-carbolinyl, phenanthridinyl, acridinyl, perimidinyl, phenanthrolinyl,phenazinyl, phenarsazinyl, phenothiazinyl, furazanyl, phenoxazinyl,isochromanyl, chromanyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl,imidazolinyl, pyrazolidinyl, pyrazolinyl, piperidinyl, piperazinyl,indolinyl, isoindolinyl, quinuclidinyl, morpholinyl or oxazolidinyl.Also included are fused ring and spiro compounds containing, forexample, the above heterocycles.

At used herein, the term “heteroaryl” refers to aromatic heterocyclicgroups. Such heteroaryl groups are preferably 5-6 membered monocylicgroups or 8-10 membered fused bicyclic groups. Examples of suchheteroaryl groups include, but are not limited to pyridyl (pyridinyl),pyrimidinyl, furanyl (furyl), thiazolyl, thienyl, pyrrolyl, pyrazolyl,imidazolyl, indolyl, isoxazolyl, oxazolyl, pyrazinyl, pyrimidinyl,pyridazinyl, benzofuranyl, benzothienyl, benzimidazolyl, quinolinyl, orisoquinolinyl.

As used herein, “pharmaceutically acceptable salts” refer to derivativesof the disclosed compounds wherein the parent compound of Formulae I-IVis modified by making acid or base salts of the compound of FormulaeI-IV. Examples of pharmaceutically acceptable salts include, but are notlimited to, mineral or organic acid salts of basic residues such asamines; alkali or organic salts of acidic residues such as carboxylicacids; and the like.

“Prodrugs” are considered to be any covalently bonded carriers whichrelease the active parent drug according to Formulae I-IV in vivo whensuch prodrug is administered to a mammalian subject. Prodrugs of thecompounds of Formulae I-IV are prepared by modifying functional groupspresent in the compounds in such a way that the modifications arecleaved, either in routine manipulation or in vivo, to the parentcompounds. Prodrugs include compounds of Formulae I-IV wherein hydroxyl,amino, sulfhydryl, or carboxyl groups are bonded to any group that, whenadministered to a mammalian subject, cleaves to form a free hydroxyl,amino, sulfhydryl, or carboxyl group respectively. Examples of prodrugsinclude, but are not limited to, acetate, formate and benzoatederivatives of alcohol and amine functional groups in the compounds ofFormulae I-IV, and the like. Examples of representative carboxyl andamino prodrugs are included under the definition of R², R³, and Y.

The pharmaceutically acceptable salts of the compounds of Formulae I-IVinclude the conventional non-toxic salts or the quaternary ammoniumsalts of the compounds of Formulae I-IV formed, for example, fromnon-toxic inorganic or organic acids. For example, such conventionalnon-toxic salts include those derived from inorganic acids such ashydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric andthe like; and the salts prepared from organic acids such as acetic,propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric,ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic,benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric,toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic,and the like.

The pharmaceutically acceptable salts of the present invention can besynthesized from the compounds of Formulae I-IV which contain a basic oracidic moiety by conventional chemical methods. Generally, the salts areprepared by reacting the free base or acid with stoichiometric amountsor with an excess of the desired salt-forming inorganic or organic acidor base in a suitable solvent or various combinations of solvents.

The pharmaceutically acceptable salts of the acids of Formulae I-IV withan appropriate amount of a base, such as an alkali or alkaline earthmetal hydroxide e.g. sodium, potassium, lithium, calcium, or magnesium,or an organic base such as an amine, e.g., dibenzylethylenediamine,trimethylamine, piperidine, pyrrolidine, benzylamine and the like, or aquaternary ammonium hydroxide such as tetramethylammoinum hydroxide andthe like.

As discussed above, pharmaceutically acceptable salts of the compoundsof the invention can be prepared by reacting the free acid or base formsof these compounds with a stoichiometric amount of the appropriate baseor acid, respectively, in water or in an organic solvent, or in amixture of the two; generally, nonaqueous media like ether, ethylacetate, ethanol, isopropanol, or acetonitrile are preferred. Lists ofsuitable salts are found in Remington's Pharmaceutical Sciences, 17thed., Mack Publishing Company, Easton, Pa., 1985, p. 1418, the disclosureof which is hereby incorporated by reference.

The disclosures of all of the references cited herein are herebyincorporated herein by reference in their entirety.

Synthesis

The compounds of the present invention can be prepared in a number ofways well known to one skilled in the art of organic synthesis. Thecompounds of the present invention can be synthesized using the methodsdescribed below, together with synthetic methods known in the art ofsynthetic organic chemistry, or variations thereof as appreciated bythose skilled in the art. Preferred methods include, but are not limitedto, those described below. All literature cited herein is incorporatedin its entirety by reference.

Compounds of Formulae I-IV can be conveniently prepared by cyclizationof aniline derived aminomethylenemalonates (Gould-Jacobs reaction, for areview of quinolone synthesis, see Radl, S.; Bouzard, D. Recent Advancesin the Synthesis of Antibacterial Quinolones. Heterocycles 1992,34:2143-2177).

Scheme I illustrates a synthetic sequence which will provide thequinolones of this invention. Reaction of a 3-Bromoaniline with diethylethoxymethylenemalonate (Albrect, R. Prog. Drug Res. 1977, 21:9) resultsin a vinylogous amide which is cyclized in diphenyl ether at reflux toafford the 7-bromoquinolone. After N¹-alkylation, the bromide isconverted to an olefin via Stille coupling to a vinyltin species or Heckolefination using styrene. Ozonolysis of the olefin provides thealdehyde.

Reductive amination of the intermediate aldehyde (for suitable methodssee, Abdel-Magid, A. F.; Maryanoff, C. A.; Carson, K. G. TetrahedronLett. 1990, 31:5595-5598, and references contained therein ) with avariety of heteroaryl amines, which may additionally contain suitableprotecting groups, provides the substituted amines. Alternatively,depending on the nature of the heterocyclic amine, the reductiveamination can be carried out in a two step procedure, wherein initialformation of an imine is carried out by treatment of the aldehyde withthe desired amine in the presence of a dehydrating agent such asmagnesium sulfate, sodium sulfate, or molecular sieves, in a suitablesolvent such as carbon tetrachloride, methylene chloride, benzene ortoluene (for example see, Modern Synthetic Reactions 2nd ed. House, H.O., Benjamin/Cummings Publishing Co., Menlo Park, Calif., 1972.). Theimine is subsequently reduced using one of a variety of reducing agentssuch as sodium borohydride, sodium cyanoborohydride, or sodiumtriacetoxyborohydride, in a suitable solvent such as methanol, ethanol,tetrahydrofuran, dioxane or 1,2-dichloroethane, to provide the desiredamine. Subsequent saponification of the ester using conventional methodsknown to one skilled in the art of organic synthesis gives the desiredacids. In the case of tert-butyl esters the acid may be produced eitherby the action of trifluoroacetic acid with or without an inert solventsuch as methylene chloride, or by the action of anhydrous HCl in asolvent such as ether or dioxane. Coupling of the resulting acids toappropriately substituted α- or β-amino esters affords an intermediatewhich can be deprotected to give compounds of Formulae I-IV. Thecoupling is carried out using any of the many methods for the formationof amide bonds known to one skilled in the art of organic synthesis.These methods include but are not limited to conversion of the acid tothe corresponding acid chloride, or use of standard coupling proceduressuch as the azide method, mixed carbonic acid anhydride (isobutylchloroformate) method, carbodiimide (dicyclohexylcarbodiimide,diisopropylcarbodiimide, or water-soluble carbodiimides) method, activeester (p-nitrophenyl ester, N-hydroxysuccinic imido ester) method,carbonyldiimidazole method, phosphorus reagents such as BOP-Cl. Some ofthese methods (especially the carbodiimide) can be enhanced by theaddition of 1-hydroxybenzotriazole. Global deprotection of the remainingprotecting groups may be accomplished by methods known to one skilled inthe art (for example see, Protective Groups in Organic Synthesis 2nd,ed.Greene, T. W., and Wuts, P. G. M., John Wiley & Sons, Inc. New York,1991.).

The compounds of the present invention wherein Y is an oxyalkoxy group,e.g. alkoxycarbonyloxyalkoxy, may be prepared by reacting a suitablyprotected carboxylic acid of Formulae I-IV with an e.g. analkoxycarbonyloxyalkyl chloride in the presence of an iodide source,such as tetrabutylammonium iodide or potassium iodide, and an acidscavenger, such as triethylamine or potassium carbonate, usingprocedures known to those skilled in the art.

As an alternative to the quinolone synthesis outlined above, thequinolone nucleus may be formed using the route illustrated in SchemeII. Similar methodology for the preparation of quinolones was firstdescribed in German patent application DE3142854. Starting from a4-bromo-3-fluoro-benzoyl chloride, condensation with malonic acidmonoethyl ester monopotassium salt gives a benzoyl acetate that issubsequently reacted with triethyl orthoformate. The resultingethoxymethylene derivative is reacted with a primary amine and cyclizedto the quinolone.

The appropriately substituted racemic β-amino acids may be purchasedcommercially or, as is shown in Scheme III, Method 1, prepared from theappropriate aldehyde, malonic acid and ammonium acetate according to theprocedure of Johnson and Livak, J. Am. Chem. Soc. 1936, 58, 299. Racemicβ-substituted-β-amino esters may be prepared through the reaction ofdialkylcuprates or alkyllithiums with 4-benzoyloxy-2-azetidinonefollowed by treatment with anhydrous ethanol (Scheme III, Method 2) orby reductive amination of β-keto esters as is described in published PCTpatent application WO9316038 (see also Rico et al., J. Org. Chem. 1993,58, 7948-51). Enantiomerically pure β-substituted-β-amino acids can beobtained through the optical resolution of the racemic mixture or can beprepared using numerous methods, including: Arndt-Eistert homologationof the corresponding a-amino acids as shown in Scheme III, Method 3 (seeMeier, and Zeller, Angew. Chem. Int. Ed. Engl. 1975, 14, 32; Rodriguez,et al. Tetrahedron Lett. 1990, 31, 5153; Greenlee, J. Med. Chem. 1985,28, 434 and references cited within); and through an enantioselectivehydrogenation of a dehydroamino acid as is shown in Scheme III, Method 4(see Asymmetric Synthesis, Vol. 5, (Morrison, ed.) Academic Press, NewYork, 1985). A comprehensive treatise on the preparation of β-amino acidderivatives may be found in published PCT patent application WO 9307867,the disclosure of which is hereby incorporated by reference.

The synthesis of N²-substituted diaminopropionic acid derivatives can becarried out via Hoffman rearrangement of a wide variety of asparaginederivatives as described in Waki, M., et al., Synthesis, 266-268,(1981).

A convenient preparation of suitably protected 2-aminoimidazoles isoutlined in Scheme IV.

Additional compounds of Formulae I-IV where R⁹ is N(R¹⁶)R¹⁷ can beprepared from the compounds of Scheme I, wherein R¹⁶ is Cbz(benzyloxycarbonyl),is shown in Scheme V. Selective removal of the Cbzgroup may be accomplished by hydrogenation using palladium on carbon ina suitable solvent such as methanol or ethanol.

The resulting amines can be converted to additional compound of FormulaeI-IV by treatment with a wide variety of reagents, for example, acylhalides, chloroformates, isocyanates, sulfonylchlorides,chlorosulfonamides, and sulfonylisocyanates, etc. using standardmethods.

Scheme VI illustrates a synthetic sequence which will provide thenaphthyridines of this invention. Reaction of 2,4-dichloronicotinic acidwith phosphorus pentachloride provides the acid chloride which reactswith ethyl malonate giving nicotinyl acetate. Reaction of nicotinylacetate with ethyl orthoformate provides ethoxyethylene malonate, whichthen reacts with the desired amine, resulting in intermediate which canbe cyclized in the presence of a base such as sodium hydride orpotassium carbonate to yield the desired 6-chloronaphthyridine. (J. Med.Chem. 1992, 35, 518-525). Coupling of the desired 6-chloronaphthyridinewith tributylvinyltin provides an olefin, 6-vinylnaphthyridine, (J.Heterocyclic chem. 1991, 28, 191) upon which further synthetictransformation as in Scheme I affords the naphthyridines of thisinvention.

The detailed processes for preparing the compounds of Formulae I-IV areillustrated by the following Examples. It is, however, understood thatthis invention is not limited to the specific details of these examples.Proton nuclear magnetic resonance spectra (¹H NMR) were measured inchloroform-d (CDCl₃) unless otherwise specified, and reported in partsper million (ppm) downfield from tetramethylsilane (TMS). The couplingpatterns are reported as follows: s, singlet; d, doublet; t, triplet; q,quartet; qt, quintet; m, multiplet.

EXAMPLE 1 1-Triphenylmethyl-2-aminoimidazole

Part A. 2-Phthalamidoimidazole

2-Aminoimidazole sulfate (2.64 g, 20 mmol) was dissolved in 200 mL ofanhydrous methanol and cooled to −78° C. A 25% solution of sodiummethoxide in methanol (4.57 mL, 20 mmol) was added dropwise. Thereaction mixture was allowed to warm to room temperature and stirred foran additional 3 h. The solution was filtered and concentrated on therotary evaporator to afford a brown oil (1.6 g, 96.4%); ¹H NMR (300 MHz,DMSO-d₆) δ5.0 (bs, 2H), 6.32, (s, 2H).

Phthalic anhydride (4.14 g, 29.2 mmol) and 2-aminoimidazole (2.32 g,29.2 mmol) were heated to 170° C. for 15 min. The crude reaction mixturewas purified using flash chromatography (gradient: chloroform :methanol=95:5-80:20) to yield 4.66 g (75%) of a brown solid; ¹H NMR (300MHz, DMSO-d₆) δ7.16 (bs, 2H), 7.94-8.06 (m, 4H), 12.35 (bs, 1H); MS(ESI) m/z 214.2 (M+H)⁺.

Part B. 1-Triphenylmethyl-2-phthalamidoimidazole

The product of Ex. 1, Part A, (4.66 g, 21.9 mmol) was dissolved in 100mL of anhydrous pyridine and triphenylmethyl chloride (9.15 g, 32.82mmol) was added. The reaction mixture was heated at reflux for 24 h.Pyridine was removed and the residue was purified using flashchromatography (chloroform : methanol 5-10%) to yield the desiredproduct (2.74 g, 27.5% yield); ¹H NMR (300 MHz, CDCl₃) δ6.80 (d, J=1.1Hz, 1H), 7.06 (t, J=7.3 Hz, 3H), 7.17 (t, J=7.7 Hz, 7H), 7.28 (d, 6H,7.64, s 4H); MS (NH₃-DCI) m/z 456 (M+H)⁺.

Part C. 1-Triphenylmethyl-2-aminoimidazole

The product of Ex. 1, Part B, (2.60 g, 5.7 mmol) and hydrazine (1.83 g,57 mmol) were heated at reflux in 250 mL of anhydrous ethanol for 1 hr.The reaction mixture was cooled and the solvent removed in vacuo. Thesolid residue was purified using flash chromatography (CHCl₃:MeOH=10:1)to yield 1.8 g (97%) of the title compound as a yellow solid; ¹H NMR(300 MHz, DMSO-d₆) δ6.26 (d, J=1.8 Hz, 1H), 6.51 (d, J=1.8 Hz, 1H), 7.13(d, J=7Hz, 6H), 7.33-7.44 (m, 9H); MS (NH3-DCI) m/z 326 (M+H)⁺.

EXAMPLE 2 3-Carboxy-1-methyl-7-[(1-triphenylmethylimidazol-2-ylamino)methyl]quinolin-4-one

Part A. 7-Bromo-3-(ethoxycarbonyl)quinolin-4-one

3-Bromoaniline (50 g, 291 mmol) and diethyl ethoxymethylenemalonate (63g, 291 mmol) were mixed together and allowed to stand at roomtemperature overnight. White crystals were filtered and recrystallizedfrom a mixture of ethyl and petroleum ether (1:1). The product was thenheated at reflux in diphenyl ether (700 mL) for 2 h. After cooling, thesolid was filtered and washed several times with ether to give acolorless solid (59.6 g, 68%) which was the mixture of isomers (93:7)wherein the desired isomer was the major component; ¹H NMR (300 MHz,DMSO-d₆) δ8.59 (s, 1H), 8.06 (d, 1H, J=g 8.8 Hz), 7.82 (d, 1H, J=1.8Hz), 7.55 (dd, 1H, J=8.8, 1.8 Hz ), 4.21 (q, 2H, J=7 Hz), 1.28 (t, 3H,J=7 Hz); MS (NH₃-CI) m/z 296 (M+H)⁺.

Part B. 7-Bromo-3-ethoxycarbonyl-1-methylquinolin-4-one

The product of Ex. 2, Part A (20 g, 68 mmol) was suspended in DMF.Methyl iodide (48.1 g, 339 mmol) and potassium carbonate (23.4 g, 170mmol) were added and reaction mixture was stirred at 60° C. overnight.The reaction mixture was poured over ice and the resulting precipitatethat was filtered and washed with water to yield a white solid (18.96 g,90 %); ¹H NMR (300 MHz, DMSO-d₆) δ8.67 (s, 1H), 8.12 (d, J=8.8 Hz, 1 H),7.97 (s, 1H), 7.66 (d, J=8.4 Hz, 1H), 4.23 (q, 2H), 1.28 (t, 3H); MS(NH₃-CI) m/z 312 (M+H)⁺.

Part C. 7-Ethenyl-3-ethoxycarbonyl-1-methylquinolin-4-one

A solution of the product of Ex. 2, Part B (0.492 g, 1.59 mmol) intoluene was degassed and kept under nitrogen. Tributylvinyltin (0.506 g,1.59 mmol) and tetrakis(triphenylphosphine)palladium(0) (37 mg, 0.032mmol) were added and the reaction mixture heated at reflux for 3 h.After cooling, the product was filtered and washed with ether to give301 mg (73 %); ¹H NMR (300 MHz, DMSO-d₆) δ8.48 (d, 1H, J=8.4 Hz), 8.45(s, 1H), 7.55 (dd, 1H, J=1.1, 8 Hz , 7.32 (d, 1H, J=1.5 Hz), 6.83 (dd,1H, J=11 Hz, 17.6 Hz), 5.95 (d, 1H, J=17.6 Hz ), 5.49 ( d, 1H, J=11 Hz),4.4 (q, 2H, J=7 Hz), 3.89 (s, 1H), 1.42 (t, 3H, J=7 Hz); MS (NH₃-CI) m/z258 (M+H)⁺.

Part D. 3-Ethoxycarbonyl-7-formyl-1-methylquinolin-4-one

The product of Ex. 2, Part C (150 mg, 0.58 mmol) and small crystal ofSudan Red was dissolved in 15 mL of dichloromethane and the reactionmixture was cooled to −78° C. Ozone was purged through the solution forabout 5 min, until the color changed from bright red to light green. Thereaction mixture was purged with nitrogen for 5 min, 0.9 mL of dimethylsulfite was added, and the reaction mixture stirred at room temperaturefor 4 h. Solvent was removed and the crude product was purified on asilica gel column eluted with gradient of 2-5% MeOH/CHCl₃ to give awhite solid (95 mg, 63%); ¹H NMR (300 MHz, DMSO-d₆) δ10.21 (s, 1H), 8.78(s, 1H), 8.39 (d, 1H, J=8.1 Hz), 8.30 (d, 1H, J=2.6 Hz), 7.93 (d, 1H,J=9.2 Hz), 4.24 (q, 2H, J=7 Hz), 4.01 (s, 3H), 1.30 (t, 3H, J=7 Hz); MS(NH₃-CI) m/z 260 (M+H)⁺.

Part E.3-Ethoxycarboxy-1-methyl-7-[(1-triphenylmethylimidazol-2-ylamino)methyl]quinolin-4-one

1-Triphenylmethyl-2-aminoimidazole (0.201 g, 0.62 mmol) and the productof Ex. 2, Part D, (0.16 g, 0.62 mmol) were heated at reflux in toluene(25 mL). The progress of the reaction was monitored by H NMR. After 6 h,the mixture was cooled to room temperature and triacetoxyborohydride(0.52 g, 2.5 mmol) was added. The reaction mixture was stirred for 24 h.Water (100 mL) was added, the organic layer was separated and the waterlayer was extracted with ethyl acetate. The combined organic layers wereconcentrated and purified by flash chromatography (MeOH/CHCl₃) to yieldthe product as a colorless solid (0.22 g, 61%); ¹H NMR (300 MHz,DMSO-d₆) δ8.63 (s, 1H), 7.98 (d, J=8.1Hz, 1H), 7.41-7.32 (m, 10H), 7.14(dd, J=6.6, 14.5 Hz, 6H), 6.73 (d, J=8.1 Hz, 1H), 6.50 (d, J=1.8 Hz,1H), 6.29 (d, J=1.8 Hz, 1H), 4.32 (d, J=5.9 Hz, 2H), 4.21 (q, J=7.3 Hz,2H), 4.02 (t, 1H), 3.79 (s, 3H), 1.28 (t, J=7.3Hz, 3H); MS (NH₃-CI) m/z569 (M+H)⁺.

Part F.3-Carboxy-1-methyl-7-[(1-triphenylmethylimidazol-2-ylamino)methyl]quinolin-4-one

A mixture of the product of Ex. 2, Part E (200 mg, 0.35 mmol), and 0.5 Mlithium hydroxide (2.1 mL, 1.0 mmol) in THF (10 mL) was stirred at roomtemperature for 3 h. Water (10 mL) was added, the volatiles wereevaporated, and the aqueous solution acidified with HCl to pH 2. Theresulting solution was extracted with CHCl₃ to give 160 mg of yellowsolid. The crude acid was purified on a silica gel column eluted with5-10% MeOH/CHCl₃ to give a white solid (113 mg, 59%); ¹H NMR (300 MHz,DMSO-d₆) δ9.0 (s, 1H), 8.11 (d, 1H, J=8 Hz), 7.56 (s, 1H), 7.31-7.2 (m,9H), 7.13 (d, 6H, J=7 Hz), 6.87 (d, 1H, J=8.4 Hz), 6.9 (d, 1H, J=1.5Hz), 6.30 (d, 1H, J=1.8 Hz), 4.39 (d, 2H, J=5.9 Hz), 4.18 (t, 1H), 3.98(s, 3H); MS (ESI) m/z 541 (M+H)⁺.

EXAMPLE 3 tert-Butyl3-amino-(2S)-[N-(2,4.6-trimethylphenyl)sulfonylamino]propionatehydrochloride

Part A. N-(2,4.6 trimethylphenyl)sulfonyl-L-asparagine

L-Asparagine (20.0 g, 0.15 mol) was suspended in a mixture oftetrahydrofuran (130 mL) and water (250 mL). Triethylamine (49 g, 0.48mol) was added followed by mesitylenesulfonyl chloride (49.7 g, 0.227mol). The reaction mixture became slightly exothermic and the solidsdissolved over a period of 0.5 h to yield a yellow solution. Thereaction mixture was stirred for 3 h at room temperature, then washedwith ether, and methylene chloride. The aqueous layer was separated, andacidified to ca. pH=1.5 with conc. HCl, during which time a thickprecipitate formed. After 0.5 h, the product was filtered, washed withwater, and dried to yield a white solid (34 g, 72%); mp: 193.5-195° C.;¹H NMR (DMSO-d₆) δ2.24 (s, 3H), 2.28 (dd, 1H), 2.45 (dd, 1H), 2.55 (s,6H), 3.98 (m, 1H), 6.88 (bs, 1H), 6.99 (s, 2H), 7.32 (bs, 1H), 7.82 (d,2H), 12.58 (bs, 1H); Mass spectrum (ESI) m/z 315.2 (M+H)⁺.

Part B. 3-Amino-(2S)—N-(2.4.6 trimethylphenyl)sulfonylaminopropionicacid

Sodium hydroxide (32 g, 0.80 mol), was dissolved in water (200 mL) andcooled in an ice bath. Bromine (19.2 g, 0.12 mol) was added dropwiseover 5 min and the mixture allowed to stir for 15 min. The product ofEx. 3, Part A, (31.44 g, 0.10 mol), was added in several portions over aperiod of ca. 10 min. during which time the yellow color faded. Thereaction mixture was gently heated on a steam bath during which time theinternal temperature rose to ca. 85° C. After 1 h, the reaction mixturewas allowed to cool to room temperature then cooled in an ice bath. Thereaction mixture was cautiously acidified to pH=6 with conc. HCl, duringwhich time a solid formed and gas was evolved. The solid was filtered,washed with cold water, and allowed to dry overnight, to yield theproduct as a white solid (23.9 g, 83%); ¹H NMR (300 MHz, DMSO-d₆) δ2.26(s, 3H), 2.59 (s, 6H), 2.80 (dd, 1H), 2.94 (dd, 1H), 3.07 (dd, 1H), 7.06(s, 2H); Mass spectrum (ESI) m/z 287.2 (M+H)⁺.

Part C. tert-Butyl3-amino-(2S)—N-(2,4,6-trimethylphenyl)sulfonylaminopropionate

The product of Ex. 3, Part B, (11.45 g, 0.04 mol), was placed in a Parrbottle, and dissolved in dioxane (170 mL), and conc. sulfuric acid (11mL) was added. The reaction mixture was cooled in a dry ice-acetone bathand ca. 185 mL of isobutylene was added. The bottle was sealed andagitated for 114 h. The bottle was de-pressurized, then purged withnitrogen for a brief time. The reaction mixture was poured into arapidly stirred mixture of water (225 mL) containing sodium hydroxide(17 g) and ether (600 mL) which had been pre-cooled in an ice bath. Thelayers were separated. The aqueous layer was extracted with additionalether. The pH of the aqueous layer was carefully adjusted with conc. HClto pH=11 and extracted four times with ether. The organic layers fromthe pH 11 adjusted extraction were combined, dried with anhydrous sodiumsulfate, filtered, and evaporated to yield the product as a viscous oilwhich solidified (8.64 g, 63%); ¹H NMR (300 MHz, CDCl₁₃) δ1.28 (s, 9H),2.28 (s, 3H), 2.67 (s, 6H), 2.93 (m, 2H), 3.69 (m, 1H), 6.95 (s, 2H).

EXAMPLE 43-[7-[(imidazol-2-ylamino)methyl]-1-methylquinoline-4-one-3-ylcarbonylamino]-(2S)-[N-(2,4,6-trimethylphenyl)sulfonylamino]propionicacid

Part A. tert-Butyl3-[7-[(imidazol-2-ylamino)methyl]-1-methylquinoline-4-one-3-ylcarbonylamino]-(2S)-[N-(2,4,6-trimethylphenyl)sulfonylamino]propionate

To a solution of the compound of Ex. 2 (150 mg, 0.28 mmol), the compoundof Ex. 3 (95 mg, 0.28 mmol), and 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TBTU,90 mg, 0.28 mmol) in DMF (10 mL) was added triethylamine (0.1 mL, 0.72mmol). The resulting mixture was stirred at room temperature overnight.Ethyl acetate was added (75 mL), and solution was washed with water(2×), saturated sodium bicarbonate, and brine. The organic layer wasdried and the solvent evaporated in vacuo to yield a yellow solid (210mg, 88%). ¹H NMR (300 MHz, DMSO-d₆) δ10.25 (t, 1H), 8.62 (s, 1H), 8.25(d, 1H, J=8 Hz), 8.02 (s 1H), 7.29-7.3 (m, 9H), 7.17-7.20 (m, 6H), 6.9(bs, 1H), 6.83 (s 2H), 6.75 (d, 1H), 6.70 (d, J=1.5 Hz, 1H), 6.45 (d,J=1.5 Hz, 1H), 6.2 (d, 1H), 4.44 (d J=5.9 Hz, 2H) 4.05 (m, 1H), 3.80 (s,3H), 3.6-3.8 (m, 2H), 2.63 (s, 6H), 2.13 (s, 3H), 1.29 (s, 9H).

Part B.3-[7-[(imidazol-2-ylamino)methyl]-1-methylquinoline-4-one-3-ylcarbonylamino]-(2S)-[N-(2,4,6-trimethylphenyl)sulfonylamino]propionicacid

The compound of Ex. 4, Part A (210 mg, 0.243 mmol) was heated at refluxovernight in trifluoroacetic acid (5 mL). The solvent was evaporated invacuo, 5 mL of water was added, and the pH was adjusted to 7. The crudeproduct was purified using reverse phase HPLC, eluting with 20-100%acetonitrile/water. Fractions containing the product were pooled,concentrated in vacuo to remove acetonitrile, and lyophilized to give awhite powder (70 mg, 42%); ¹H NMR (300 MHz, DMSO-d₆) δ12.37 (s, 2H),9.95 (t, 1H), 8.70 (t, 1H), 8.63 (s, 1H), 8.33 (d, 1H, J=8.4 Hz), 8.10(d, 1H, J=8.8 Hz), 7.82 (s, 1H), 7.55 (d, 1H, J=8 Hz), 7.01 (s, 2H),6.61 (s, 2H), 4.69 (d, 2H, J=6.2 Hz), 3.99 (s, 3H), 3.9 (m, 1H), 3.7 (m,2H), 2.47 (s, 6H), 1.76 (s, 3H); MS (ESI) m/z 567 (M+H)⁺.

The examples listed in Table 1 were prepared in an analogous fashion tothat described in Example 4.

TABLE 1

MS Ex. R¹ U R² (M + H)⁺ 5 imidazol-2-yl NHCH₂ Ph(2,6-Cl₂) 593 6imidazol-2-yl NHCH₂ Ph(2,6-Cl₂-4-Ph) 669 7 imidazol-2-yl NHCH₂Ph(2,4,6-Me₃) 567 8 amino(imino)- NHCH₂ Ph(2,6-Cl₂) 569 methyl 9amino(imino)- NHCH₂ Ph(2,4,6-Me₃) 543 methyl 10 imidazolin-2-yl NHCH₂Ph(2,6-Cl₂) 595 11 tetrahydro- NHCH₂ Ph(2,4,6-Me₃) 583 pyrimidin-2-yl 12imidazolin-2-yl NHCH₂ Ph(2,4,6-Me₃) 569 13 imidazol-2-yl NHCH₂Ph(2,6-Me₂-4-Ph) 629 14 imidazoi-2-yl NHCH₂ isoxazol-4- 544 yl (3,5-Me₂)

Utility

The compounds of Formula I-IV of the present invention possess activityas antagonists of integrins such as, for example, the α_(v)β₃ orvitronectin receptor, α_(v)β₅ or α₅β₁, and such have utility in thetreatment and diagnosis of cell adhesion, angiogenic disorders,inflammation, bone degradation, cancer metastases, diabetic retinopathy,thrombosis, restenosis, macular degeneration, and other conditionsmediated by cell adhesion and/or cell migration and/or angiogenesis. Theintegrin antagonist activity of the compounds of the present inventionis demonstrated using assays which measure the binding of a specificintegrin to a native ligand, for example, using the ELISA assaydescribed below for the binding of vitronectin to the α_(v)β₃ receptor.

The compounds of the present invention possess selectivity for theα_(v)β₃ receptor relative to the GPIIb/IIIa receptor as demonstrated bytheir reduced activity in standard assays of platelet aggregation, suchas the platelet aggregation assay described below.

One of the major roles of integrins in vivo is to mediate cellularinteractions with adjacent cells. Cell based adhesion assays can be usedto mimic these interactions in vitro. A cell based assay is morerepresentative of the in vivo situation than an ELISA since the receptoris maintained in membranes in the native state. The compounds of thepresent invention have activity in cell-based assays of adhesion, forexample as demonstrated in using the cell adhesion assays describedbelow.

The compounds of Formula I-IV of the present invention may be useful forthe treatment or prevention of other diseases which involve celladhesion processes, including, but not limited to, osteoporosis,rheumatoid arthritis, autoimmune disorders, bone degradation, rheumatoidarthritis, asthma, allergies, adult respiratory distress syndrome, graftversus host disease, organ transplantation, septic shock, psoriasis,eczema, contact dermatitis, osteoarthritis, atherosclerosis, metastasis,wound healing, inflammatory bowel disease and other angiogenicdisorders.

The compounds of Formula I-IV have the ability to suppress/inhibitangiogenesis in vivo, for example, as demonstrated using animal modelsof ocular neovascularization.

The compounds provided by this invention are also useful as standardsand reagents in determining the ability of a potential pharmaceutical toinhibit integrin-ligand binding. These may be provided in a commercialkit comprising a compound of this invention.

As used herein “μg” denotes microgram, “mg” denotes milligram, “g”denotes gram, “μL” denotes microliter, “mL” denotes milliliter, “L”denotes liter, “nM” denotes nanomolar, “μM” denotes micromolar, “Mm”denotes millimolar, “M” denotes molar and “nm” denotes nanometer.“Sigma” stands for the Sigma-Aldrich Corp. of St. Louis, Mo.

The utility of the compounds of the present invention may be assessed bytesting in one or more of the following assays as described in detailbelow: Purified α_(v)β₃ (human placenta)—Vitronectin ELISA,α_(v)β₃-Vitronectin Binding Assay, Human Aortic Smooth Muscle CellMigration Assay, In Vivo Angiogenesis Model, Pig Restenosis Model, MouseRetinopathy Model. A compound of the present invention is considered tobe active if it has an IC₅₀ or K_(i) value of less than about 10 μM forthe inhibition of α_(v)β₃-Vitronectin Binding Assay, with compoundspreferably having K_(i) values of less than about 0.1 μM. Testedcompounds of the present invention are active in the α_(v)β₃-VitronectinBinding Assay.

Purified α_(v)β₃ (human placenta)—Vitronectin ELISA

The α_(v)β₃ receptor was isolated from human placental extracts preparedusing octylglucoside. The extracts were passed over an affinity columncomposed of anti-α_(v)β₃ monoclonal antibody (LM609) bound to Affigel.The column was subsequently washed extensively at pH 7 and pH 4.5followed by elution at pH 3. The resulting sample was concentrated bywheat germ agglutinin chromatography to provide two bands by SDS gelelectrophoresis which were confirmed as α_(v)β₃ by western blotting.

Affinity purified protein was diluted at different levels and plated to96 well plates. ELISA was performed using fixed concentration ofbiotinylated vitronectin (approximately 80 nM/well). This receptorpreparation contains the α_(v)β₃ with no detectable levels of α_(v)β₅according to the gel and according to effects of blocking antibodies forthe α_(v)β₃ or α_(v)β₅ integrins in the ELISA.

A submaximal concentration of biotinylated vitronectin was selectedbased on a concentration response curve with fixed receptorconcentration and variable concentrations of biotinylated vitronectin.

α_(v)β₃-Vitronectin Binding Assay

The purified receptor is diluted with coating buffer (20 mM Tris HCl,150 mM NaCl, 2.0 mM CaCl₂, 1.0 mM MgCl₂.6H₂O, 1.0 mM MnCl₂.4H₂O) andcoated (100 μL/well) on Costar (3590) high capacity binding platesovernight at 4° C. The coating solution is discarded and the plateswashed once with blocking/binding buffer (B/B buffer, 50 mM Tris HCl,100 mM NaCl, 2.0 mM CaCl₂, 1.0 mM MgCl₂.6H₂O, 1.0 mM MnCl₂.4H₂O).Receptor is then blocked (200 μL/well) with 3.5% BSA in B/B buffer for 2hours at room temperature. After washing once with 1.0% BSA in B/Bbuffer, biotinylated vitronectin (100 μL) and either inhibitor (11 μL)or B/B buffer w/1.0% BSA (11 μL)is added to each well. The plates areincubated 2 hours at room temperature. The plates are washed twice withB/B buffer and incubated 1 hour at room temperature with anti-biotinalkaline phosphatase (100 μL/well) in B/B buffer containing 1.0% BSA.The plates are washed twice with B/B buffer and alkaline phosphatasesubstrate (100 μL) is added. Color is developed at room temperature.Color development is stopped by addition of 2N NaOH (25 μL/well) andabsorbance is read at 405 nm. The IC₅₀ is the concentration of testsubstance needed to block 50% of the vitronectin binding to thereceptor.

Integrin Cell-Based Adhesion Assays

In the adhesion assays, a 96 well plate was coated with the ligand(i.e., fibrinogen) and incubated overnight at 4° C. The following day,the cells were harvested, washed and loaded with a fluorescent dye. Testcompounds and cells were added together and then were immediately addedto the coated plate. After incubation, loose cells are removed from theplate, and the plate (with adherent cells) is counted on a fluorometer.The ability of test compounds to inhibit cell adhesion by 50% is givenby the IC₅₀ value and represents a measure of potency of inhibition ofintegrin mediated binding. Compounds were tested for their ability toblock cell adhesion using assays specific for α_(v)β₃, α_(v)β₅ and α₅β₁integrin interactions.

Platelet Aggregation Assay

Venous blood was obtained from anesthetized mongrel dogs or from healthyhuman donors who were drug- and aspirin-free for at least two weeksprior to blood collection. Blood was collected into citrated Vacutainertubes. The blood was centrifuged for 15 minutes at 150×g (850 RPM in aSorvall RT6000 Tabletop Centrifuge with H-1000 B rotor) at roomtemperature, and platelet-rich plasma (PRP) was removed. The remainingblood was centrifuged for 15 minutes at 1500×g (26,780 RPM) at roomtemperature, and platelet-poor plasma (PPP) was removed. Samples wereassayed on a PAP-4 Platelet Aggregation Profiler, using PPP as the blank(100% transmittance). 200 μL of PRP (5×10⁸ platelets/mL) were added toeach micro test tube, and transmittance was set to 0%. 20 μL of ADP (10μM) was added to each tube, and the aggregation profiles were plotted (%transmittance versus time). Test agent (20 μL) was added at differentconcentrations prior to the addition of the platelet agonist. Resultsare expressed as % inhibition of agonist-induced platelet aggregation.

Human Aortic Smooth Muscle Cell Migration Assay

A method for assessing α_(v)β₃-mediated smooth muscle cell migration andagents which inhibit α_(v)β₃-mediated smooth muscle cell migration isdescribed in Liaw et al., J. Clin. Invest. (1995) 95: 713-724).

In Vivo Angiogenesis Model

A quantitative method for assessing angiogenesis and antiangiogenicagents is described in Passaniti et al., Laboratory Investigation (1992)67: 519-528

Pig Restenosis Model

A method for assessing restenosis and agents which inhibit restenosis isdescribed in Schwartz et al., J. Am. College of Cardiology (1992) 19:267-274.

Mouse Retinopathy Model

A method for assessing retinopathy and agents which inhibit retinopathyis described in Smith et al., Invest. Ophthal. & Visual Science (1994)35: 101-111.

Dosage and Formulation

The compounds of this invention can be administered by any means thatproduces contact of the active agent with the agent's site of action,the α_(v)β₃ integrin, in the body of a mammal. They can be administeredby any conventional means available for use in conjunction withpharmaceuticals, either as individual therapeutic agents or in acombination of therapeutic agents, such as a antiplatelet agent such asaspirin, piroxicam, or ticlopidine which are agonist-specific, or ananti-coagulant such as warfarin or heparin, or a thrombin inhibitor suchas a boropeptide, hirudin or argatroban, or a thrombolytic agent such astissue plasminogen activator, anistreplase, urokinase or streptokinase,or combinations thereof. The compounds of the invention, or compounds ofthe invention in combination with other therapeutic agents, can beadministered alone, but generally administered with a pharmaceuticalcarrier selected on the basis of the chosen route of administration andstandard pharmaceutical practice.

The dosage of the novel compounds of this invention administered will,of course, vary depending upon known factors, such as thepharmacodynamic characteristics of the particular agent and its mode androute of administration; the age, health and weight of the recipient;the nature and extent of the symptoms; the kind of concurrent treatment;the frequency of treatment; and the effect desired. A daily dosage ofactive ingredient can be expected to be about 0.001 to 10 milligrams perkilogram of body weight.

Dosage forms (compositions suitable for administration) contain fromabout 0.1 milligram to about 100 milligrams of active ingredient perunit. In these pharmaceutical compositions the active ingredient willordinarily be present in an amount of about 0.5-95% by weight based onthe total weight of the composition.

The active ingredient can be administered orally in solid dosage forms,such as capsules, tablets, and powders, or in liquid dosage forms, suchas elixirs, syrups, and suspensions. It can also be administeredparenterally, in sterile liquid dosage forms.

Gelatin capsules contain the active ingredient and powdered carriers,such as lactose, starch, cellulose derivatives, magnesium stearate,stearic acid, and the like. Similar diluents can be used to makecompressed tablets. Both tablets and capsules can be manufactured assustained release products to provide for continuous release ofmedication over a period of hours. Compressed tablets can be sugarcoated or film coated to mask any unpleasant taste and protect thetablet from the atmosphere, or enteric coated for selectivedisintegration in the gastrointestinal tract.

Liquid dosage forms for oral administration can contain coloring andflavoring to increase patient acceptance.

In general, water, a suitable oil, saline, aqueous dextrose (glucose),and related sugar solutions and glycols such as propylene glycol orpolyethylene glycols are suitable carriers for parenteral solutions.Solutions for parenteral administration preferably contain a watersoluble salt of the active ingredient, suitable stabilizing agents, andif necessary, buffer substances. Antioxidizing agents such as sodiumbisulfite, sodium sulfite, or ascorbic acid, either alone or combined,are suitable stabilizing agents. Also used are citric acid and its saltsand sodium EDTA. In addition, parenteral solutions can containpreservatives, such as benzalkonium chloride, methyl- or propyl-paraben,and chlorobutanol.

Suitable pharmaceutical carriers are described in Remington'sPharmaceutical Sciences, Mack Publishing Company, a standard referencetext in this field.

Useful pharmaceutical dosage-forms for administration of the compoundsof this invention can be illustrated as follows:

Capsules

A large number of unit capsules are prepared by filling standardtwo-piece hard gelatin capsules each with 10 milligrams of powderedactive ingredient, 150 milligrams of lactose, 50 milligrams ofcellulose, and 6 milligrams magnesium stearate.

Soft Gelatin Capsules

A mixture of active ingredient in a digestable oil such as soybean oil,cottonseed oil or olive oil is prepared and injected by means of apositive displacement pump into gelatin to form soft gelatin capsulescontaining 10 milligrams of the active ingredient. The capsules arewashed and dried.

Tablets

A large number of tablets are prepared by conventional procedures sothat the dosage unit was 10 milligrams of active ingredient 0.2milligrams of colloidal silicon dioxide, 5 milligrams of magnesiumstearate, 275 milligrams of microcrystalline cellulose, 11 milligrams ofstarch and 98.8 milligrams of lactose. Appropriate coatings may beapplied to increase palatability or delay absorption.

The combination products of this invention, such as the novel α_(v)β₃antagonist compounds of this invention in combination with aanti-coagulant agent such as warfarin or heparin, or an anti-plateletagent such as aspirin, piroxicam or ticlopidine, or a thrombin inhibitorsuch as a boropeptide, hirudin or argatroban, or a thrombolytic agentsuch as tissue plasminogen activator, anistreplase, urokinase orstreptokinase, or combinations thereof, can be in any dosage form, suchas those described above, and can also be administered in various ways,as described above.

In a preferred embodiment, the combination products of the invention areformulated together, in a single dosage form (that is, combined togetherin one capsule, tablet, powder, or liquid, etc.). When the combinationproducts are not formulated together in a single dosage form, theα_(v)β₃ antagonist compounds of this invention and the anti-coagulantagent, anti-platelet agent, thrombin inhibitor, and/or thrombolyticagent may be administered at the same time (that is, together), or inany order, for example the compounds of this invention are administeredfirst, followed by administration of the anti-coagulant agent,anti-platelet agent, thrombin inhibitor, and/or thrombolytic agent. Whennot administered at the same time, preferably the administration of thecompound of this invention and any anti-coagulant agent, anti-plateletagent, thrombin inhibitor, and/or thrombolytic agent occurs less thanabout one hour apart, more preferably less than about 30 minutes apart,even more preferably less than about 15 minutes apart, and mostpreferably less than about 5 minutes apart. Preferably, administrationof the combination products of the invention is oral. The terms oralagent, oral inhibitor, oral compound, or the like, as used herein,denote compounds which may be orally administered. Although it ispreferable that the α_(v)β₃ antagonist compounds of this invention andthe anti-coagulant agent, anti-platelet agent, thrombin inhibitor,and/or thrombolytic agent are both administered in the same fashion(that is, for example, both orally), if desired, they may each beadministered in different fashions (that is, for example, one componentof the combination product may be administered orally, and anothercomponent may be administered intravenously). The dosage of thecombination products of the invention may vary depending upon variousfactors such as the pharmacodynamic characteristics of the particularagent and its mode and route of administration, the age, health andweight of the recipient, the nature and extent of the symptoms, the kindof concurrent treatment, the frequency of treatment, and the effectdesired, as described above.

As discussed above, where two or more of the foregoing therapeuticagents are combined or co-administered with the compounds of thisinvention, generally the amount of each component in a typical dailydosage and typical dosage form may be reduced relative to the usualdosage of the agent when administered alone, in view of the additive orsynergistic effect which would be obtained as a result of addition offurther agents in accordance with the present invention.

Particularly when provided as a single dosage form, the potential existsfor a chemical interaction between the combined active ingredients (forexample, a novel compound of this invention and an anti-coagulant suchas warfarin or heparin, or a novel compound of this invention and ananti-platelet agent such as aspirin, piroxicam or ticlopidine, or anovel compound of this invention and a thrombin inhibitor such as aboropeptide, hirudin or argatroban, or a novel compound of thisinvention and a thrombolytic agent such as tissue plasminogen activator,anistreplase, urokinase or streptokinase, or combinations thereof). Forthis reason, the preferred dosage forms of the combination products ofthis invention are formulated such that although the active ingredientsare combined in a single dosage form, the physical contact between theactive ingredients is minimized (that is, reduced).

In order to minimize contact, one embodiment of this invention where theproduct is orally administered provides for a combination productwherein one active ingredient is enteric coated. By enteric coating oneof the active ingredients, it is possible not only to minimize thecontact between the combined active ingredients, but also, it ispossible to control the release of one of these components in thegastrointestinal tract such that one of these components is not releasedin the stomach but rather is released in the intestines. Anotherembodiment of this invention where oral administration is desiredprovides for a combination product wherein one of the active ingredientsis coated with a sustained-release material which effects asustained-release throughout the gastrointestinal tract and also servesto minimize physical contact between the combined active ingredients.Furthermore, the sustained-released component can be additionallyenteric coated such that the release of this component occurs only inthe intestine. Still another approach would involve the formulation of acombination product in which the one component is coated with asustained and/or enteric release polymer, and the other component isalso coated with a polymer such as a low viscosity grade ofhydroxypropyl methylcellulose (HPMC) or other appropriate materials asknown in the art, in order to further separate the active components.The polymer coating serves to form an additional barrier to interactionwith the other component.

Dosage forms of the combination products of the present inventionwherein one active ingredient is enteric coated can be in the form oftablets such that the enteric coated component and the other activeingredient are blended together and then compressed into a tablet orsuch that the enteric coated component is compressed into one tabletlayer and the other active ingredient is compressed into an additionallayer. Optionally, in order to further separate the two layers, one ormore placebo layers may be present such that the placebo layer isbetween the layers of active ingredients. In addition, dosage forms ofthe present invention can be in the form of capsules wherein one activeingredient is compressed into a tablet or in the form of a plurality ofmicrotablets, particles, granules or non-perils, which are then entericcoated. These enteric coated microtablets, particles, granules ornon-perils are then placed into a capsule or compressed into a capsulealong with a granulation of the other active ingredient.

These as well as other ways of minimizing contact between the componentsof combination products of the present invention, whether administeredin a single dosage form or administered in separate forms but at thesame time by the same manner, will be readily apparent to those skilledin the art, once armed with the present disclosure.

Pharmaceutical kits useful in, for example, the inhibition of thrombusformation, the prevention of blood clots, and/or the treatment ofthromboembolic disorders, which comprise a therapeutically effectiveamount of a compound according to the method of the present inventionalong with a therapeutically effective amount of an anti-coagulant agentsuch as warfarin or heparin, or an anti-platelet agent such as aspirin,piroxicam or ticlopidine, or a thrombin inhibitor such as a boropeptide,hirudin or argatroban, or a thrombolytic agent such as tissueplasminogen activator, anistreplase, urokinase or streptokinase, orcombinations thereof, in one or more sterile containers, are also withinthe ambit of the present invention. Sterilization of the container maybe carried out using conventional sterilization methodology well knownto those skilled in the art. The sterile containers of materials maycomprise separate containers, or one or more multi-part containers, asexemplified by the UNIVIAL™ two-part container (available from AbbottLabs, Chicago, Ill.), as desired. The compounds according to the methodof the invention and the anti-coagulant agent, anti-platelet agent,thrombin inhibitor, thrombolytic agent, and/or combinations thereof, maybe separate, or combined into a single dosage form as described above.Such kits may further include, if desired, one or more of variousconventional pharmaceutical kit components, such as for example, one ormore pharmaceutically acceptable carriers, additional vials for mixingthe components, etc., as will be readily apparent to those skilled inthe art. Instructions, either as inserts or as labels, indicatingquantities of the components to be administered, guidelines foradministration, and/or guidelines for mixing the components, may also beincluded in the kit.

What is claimed is:
 1. A compound of Formula IV:

including stereoisomeric forms thereof, or mixtures of stereoisomericforms thereof, or pharmaceutically acceptable salt forms thereofwherein: R¹ is selected from:

R² and R³ are independently selected from: H, C₁-C₄ alkoxy, NR¹¹R¹²,halogen, NO₂, CN, CF₃, C₁-C₆ alkyl, C₃-C₆ alkenyl, C₃-C₇ cycloalkyl,C₃-C₇ cycloalkyl(C₁-C₄ alkyl), aryl(C₁-C₆ alkyl)-, (C₁-C₆alkyl)carbonyl, (C₁-C₆ alkoxy)carbonyl, arylcarbonyl, and arylsubstituted with 0-4 R⁷; alternatively, when R² and R³ are substituentson adjacent atoms, they can be taken together with the carbon atoms towhich they are attached to form a 5-7 membered carbocyclic or 5-7membered heterocyclic aromatic or nonaromatic ring system, saidcarbocyclic or heterocyclic ring being substituted with 0-2 groupsselected from C₁-C₄ alkyl, C₁-C₄ alkoxy, halo, cyano, amino, CF₃ andNO₂; R^(2a) is selected from: H, C₁-C₁₀ alkyl, C₂-C₆ alkenyl, C₃-C₁₁cycloalkyl, C₃-C₇ cycloalkyl(C₁-C₄ alkyl), aryl, aryl(C₁-C₄ alkyl)-,(C₂-C₇ alkyl)carbonyl, arylcarbonyl, (C₂-C₁₀ alkoxy)carbonyl, C₃-C₇cycloalkoxycarbonyl, C₇-C₁₁ bicycloalkoxycarbonyl, aryloxycarbonyl,aryl(C₁-C₁₀ alkoxy)carbonyl, C₁-C₆ alkylcarbonyloxy(C₁-C₄alkoxy)carbonyl, arylcarbonyloxy(C₁-C₄ alkoxy)carbonyl, and C₃-C₇cycloalkylcarbonyloxy(C₁-C₄ alkoxy)carbonyl; R⁴ is selected from: H,C₁-C₆ alkyl, C₃-C₇ cycloalkyl, C₃-C₇ cycloalkyl(C₁-C₄ alkyl)-, aryl,heteroaryl, aryl(C₁-C₆ alkyl)-, and heteroaryl(C₁-C₆ alkyl)-, whereinsaid aryl or heteroaryl groups are substituted with 0-2 substituentsindependently selected from the group consisting of C₁-C₄ alkyl, C₁-C₄alkoxy, F, Cl, Br, CF₃, and NO₂; R⁶ is selected from: H, C₁-C₁₀ alkyl,hydroxy, C₁-C₁₀ alkoxy, nitro, C₁-C₁₀ alkylcarbonyl, —N(R¹¹)R¹², cyano,halo, CF₃, CHO, CO₂R^(18b), C(═O)R^(18b), CONR¹⁷R^(18b), OC(═O)R¹⁰,OR¹⁰, OC(═O)NR¹⁰R¹¹, NR¹⁰C(═O)R¹⁰, NR¹⁰C(═O)OR²¹, NR¹⁰C(═O)NR¹⁰R¹¹,NR¹⁰SO₂NR¹⁰R¹¹, NR¹⁰SO₂R²¹, S(O)_(p)R¹¹, SO₂NR¹⁰R¹¹, aryl substitutedwith 0-3 groups selected from halogen, C₁-C₆ alkoxy, C₁-C₆ alkyl, CF₃,S(O)_(m)Me, and —NMe₂, aryl(C₁-C₄ alkyl)-, said aryl being substitutedwith 0-3 groups selected from halogen, C₁-C₆ alkoxy, C₁-C₆ alkyl, CF₃,S(O)_(p)Me, and —NMe₂, and a 5-10 membered heterocyclic ring containing1-3 N, O, or S heteroatoms, wherein said heterocyclic ring may besaturated, partially saturated, or fully unsaturated, said heterocyclicring being substituted with 0-2 R⁷; R⁷ is selected from: H, hydroxy,C₁-C₄ alkyl, C₁-C₄ alkoxy, aryl, aryl(C₁-C₄ alkyl)-, (C₁-C₄alkyl)carbonyl, CO₂R^(18a), SO₂R¹¹, SO₂NR¹⁰R¹¹, OR¹⁰, and N(R¹¹)R¹²; Uis selected from: —(CH₂)_(n)—, —(CH₂)_(n)O(CH₂)_(m)—, —NH(CH₂)_(n)—,—N(R¹⁰)C(═O)—, —NHC(═O)(CH₂)_(n)—, and —C(═O)N(R¹⁰)—; G is N; R⁸ isselected from: H, CO₂R^(18b), C(═O)R^(18b), CONR¹⁷R^(18b), C₁-C₁₀ alkylsubstituted with 0-1 R⁶, C₂-C₁₀ alkenyl substituted with 0-1 R⁶, C₂-C₁₀alkynyl substituted with 0-1 R⁶, C₃-C₈ cycloalkyl substituted with 0-1R⁶, C₅-C₆ cycloalkenyl substituted with 0-1 R⁶, (C₁-C₁₀ alkyl)carbonyl,C₃-C₁₀ cycloalkyl(C₁-C₄ alkyl)-, phenyl substituted with 0-3 R⁶,naphthyl substituted with 0-3 R⁶, a 5-10 membered heterocyclic ringcontaining 1-3 N, O, or S heteroatoms, wherein said heterocyclic ringmay be saturated, partially saturated, or fully unsaturated, saidheterocyclic ring being substituted with 0-2 R⁷; R⁹ is selected from:C₁-C₁₀ alkyl substituted with 0-1 R⁶, C₁-C₁₀ alkoxy substituted with 0-2R⁷, H, nitro, N(R¹¹)R¹², OC(═O)R¹⁰, OR¹⁰, OC(═O)NR¹⁰R¹¹, NR¹⁰C(═O)R¹⁰,NR¹⁰C(═O)OR²¹, NR¹⁰C(═O)NR¹⁰R¹¹, NR¹⁰SO₂NR¹⁰R¹¹, NR¹⁰SO₂R²¹, hydroxy,OR²², —N(R¹⁰)R¹¹, —N(R¹⁶)R¹⁷, aryl(C₀-C₆ alkyl)carbonyl, aryl(C₁-C₆alkyl), heteroaryl(C₁-C₆ alkyl), CONR^(18a)R²⁰, SO₂R^(18a), andSO₂NR^(18a)R²⁰, providing that any of the above alkyl, aryl orheteroaryl groups may be unsubstituted or substituted independently with1-2 R⁷; R¹⁰ is selected from: H, CF₃, C₃-C₆ alkenyl, C₃-C₁₁ cycloalkyl,aryl, (C₃-C₁₁ cycloalkyl)methyl, aryl(C₁-C₄ alkyl), and C₁-C₁₀ alkylsubstituted with 0-2 R⁶; R¹¹ is selected from: H, hydroxy, C₁-C₈ alkyl,C₃-C₆ alkenyl, C₃-C₁₁ cycloalkyl, (C₃-C₁₁ cycloalkyl)methyl, C₁-C₆alkoxy, benzyloxy, aryl, heteroaryl, heteroaryl(C₁-C₄ alkyl)-,aryl(C₁-C₄ alkyl), adamantylmethyl, and C₁-C₁₀ alkyl substituted with0-2 R⁴; R¹² is selected from: H, C₁-C₆ alkyl, triphenylmethyl,methoxymethyl, methoxyphenyldiphenylmethyl, trimethylsilylethoxymethyl,(C₁-C₆ alkyl)carbonyl, (C₁-C₆ alkoxy)carbonyl, (C₁-C₆alkyl)aminocarbonyl, C₃-C₆ alkenyl, C₃-C₇ cycloalkyl, C₃-C₇cycloalkyl(C₁-C₄ alkyl)-, aryl, heteroaryl(C₁-C₆ alkyl)carbonyl,heteroarylcarbonyl, aryl(C₁-C₆ alkyl)-, (C₁-C₆ alkyl)carbonyl,arylcarbonyl, C₁-C₆ alkylsulfonyl, arylsulfonyl, aryl(C₁-C₆alkyl)sulfonyl, heteroarylsulfonyl, heteroaryl(C₁-C₆ alkyl)sulfonyl,aryloxycarbonyl, and aryl(C₁-C₆ alkoxy)carbonyl, wherein said arylgroups are substituted with 0-2 substituents selected from the groupconsisting of C₁-C₄ alkyl, C₁-C₄ alkoxy, halo, CF₃, and nitro; R¹⁶ isselected from: —C(═O)OR^(8a), —C(═O)R^(18b), —C(═O)N(R^(18b))₂,—SO₂R^(18a), and —SO₂N(R^(18b))₂; R¹⁷ is selected from: H, C₁-C₆ alkyl,C₃-C₇ cycloalkyl, C₃-C₇ cycloalkyl(C₁-C₄ akyl)-, aryl, aryl(C₁-C₆alkyl)-, and heteroaryl(C₁-C₆ alkyl); R^(18a) is selected from: C₁-C₈alkyl, C₃-C₁₁ cycloalkyl, aryl(C₁-C₆ alkyl)-, said aryl substituted with0-4 R¹⁹, heteroaryl(C₁-C₆ alkyl)-, said heteroaryl substituted with 0-4R¹⁹, (C₁-C₆ alkyl)heteroaryl, said heteroaryl substituted with 0-4 R¹⁹,heteroaryl substituted with 0-4 R¹⁹, phenyl substituted with 0-4 R¹⁹,and naphthyl substituted with 0-4 R¹⁹; R^(18b) is H or R^(18a); R¹⁹ isselected from: H, halogen, CF₃, CO₂H, CN, NO₂, —NR¹¹R¹², OCF₃, C₁-C₈alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₁₁ cycloalkyl, C₃-C₇cycloalkyl(C₁-C₄ alkyl)-, aryl(C₁-C₆ alkyl)-, C₁-C₆ alkoxy, C₁-C₄alkoxycarbonyl, aryl, aryl-O—, aryl-SO₂—, heteroaryl, andheteroaryl-SO₂—, wherein said aryl and heteroaryl groups are substitutedwith 0-4 groups selected from hydrogen, halogen, CF₃, C₁-C₃ alkyl, andC₁-C₃ alkoxy; R²⁰ is selected from: hydroxy, C₁-C₁₀ alkyloxy, C₃-C₁₁cycloalkyloxy, aryloxy, aryl(C₁-C₄ alkyl)oxy, C₂-C₁₀alkylcarbonyloxy(C₁-C₂ alkyl)oxy-, C₂-C₁₀ alkoxycarbonyloxy(C₁-C₂alkyl)oxy-, C₂-C₁₀ alkoxycarbonyl(C₁-C₂ alkyl)oxy-, C₃-C₁₀cycloalkylcarbonyloxy(C₁-C₂ alkyl)oxy-, C₃-C₁₀cycloalkoxycarbonyloxy(C₁-C₂ alkyl)oxy-, C₃-C₁₀cycloalkoxycarbonyl(C₁-C₂ alkyl)oxy-, aryloxycarbonyl(C₁-C₂ alkyl)oxy-,aryloxycarbonyloxy(C₁-C₂ alkyl)oxy-, arylcarbonyloxy(C₁-C₂ alkyl)oxy-,C₁-C₅ alkoxy(C₁-C₅ alkyl)carbonyloxy(C₁-C₂ alkyl)oxy-, (5-(C₁-C₅alkyl)-1,3-dioxa-cyclopenten-2-one-yl)methyloxy,(5-aryl-1,3-dioxa-cyclopenten-2-one-yl)methyloxy, and(R¹⁰)(R¹¹)N—(C₁-C₁₀ alkoxy)-; R²¹ is selected from: C₁-C₈ alkyl, C₂-C₆alkenyl, C₃-C₁₁ cycloalkyl, (C₃-C₁₁ cycloalkyl)methyl, aryl, aryl(C₁-C₄alkyl)-, and C₁-C₁₀ alkyl substituted with 0-2 R⁷; R²² is selected from:—C(═O)—R^(18b), —C(═O)N(R^(18b))₂, —C(═O)NHSO₂R^(18a),—C(═O)NHC(═O)R^(18b), —C(═O)NHC(═O)OR^(18a), and —C(═O) NHSO₂NHR^(18b);m is 0-2; n is 0-4; and p is 0-2; with the following proviso: (1) n andm are chosen such that the number of atoms connecting R¹ and —COR²⁰ inFormula (IV) is in the range of 10-14.
 2. A compound of claim 1 ofFormula IV:

including stereoisomeric forms thereof, or mixtures of stereoisomericforms thereof, or pharmaceutically acceptable salt forms thereofwherein: R¹ is selected from:

R² and R³ are independently selected from: H, C₁-C₄ alkoxy, NR¹¹R¹²,halogen, NO₂, CN, CF₃, C₁-C₆ alkyl, C₃-C₆ alkenyl, C₃-C₇ cycloalkyl,C₃-C₇ cycloalkyl(C₁-C₄ alkyl), aryl(C₁-C₆ alkyl)-, (C₁-C₆alkyl)carbonyl, (C₁-C₆ alkoxy)carbonyl, arylcarbonyl, and arylsubstituted with 0-4 R⁷; alternatively, when R² and R³ are substituentson adjacent atoms, they can be taken together with the carbon atoms towhich they are attached to form a 5-7 membered carbocyclic or 5-7membered heterocyclic aromatic or nonaromatic ring system, saidcarbocyclic or heterocyclic ring being substituted with 0-2 groupsselected from C₁-C₄ alkyl, C₁-C₄ alkoxy, halo, cyano, amino, CF₃ andNO₂; R^(2a) is selected from: H, C₁-C₁₀ alkyl, C₂-C₆ alkenyl, C₃-C₁₁cycloalkyl, C₃-C₇ cycloalkyl(C₁-C₄ alkyl), aryl, aryl(C₁-C₄ alkyl)-,(C₂-C₇ alkyl)carbonyl, arylcarbonyl, (C₂-C₁₀ alkoxy)carbonyl, C₃-C₇cycloalkoxycarbonyl, C₇-C₁₁ bicycloalkoxycarbonyl, aryloxycarbonyl,aryl(C₁-C₁₀ alkoxy)carbonyl, C₁-C₆ alkylcarbonyloxy(C₁-C₄alkoxy)carbonyl, arylcarbonyloxy(C₁-C₄ alkoxy)carbonyl, and C₃-C₇cycloalkylcarbonyloxy(C₁-C₄ alkoxy)carbonyl; R⁴ is selected from: H,C₁-C₄ alkyl, C₃-C₇ cycloalkyl, C₃-C₇ cycloalkyl(C₁-C₄ akyl)-, aryl,heteroaryl, aryl(C₁-C₄ alkyl)-, and heteroaryl(C₁-C₄ alkyl)-, whereinsaid aryl or heteroaryl groups are substituted with 0-2 substituentsindependently selected from the group consisting of C₁-C₄ alkyl, C₁-C₄alkoxy, F, Cl, Br, CF₃, and NO₂; R⁶ is selected from: H, C₁-C₄ alkyl,hydroxy, C₁-C₄ alkoxy, nitro, C₁-C₄ alkylcarbonyl, —N(R¹¹)R¹², cyano,halo, CF₃, CHO, CO₂R^(18b), C(═O)R^(18b), CONR¹⁷R^(18b), OC(═O)R¹⁰,OR¹⁰, OC(═O)NR¹⁰R¹¹, NR¹⁰C(═O)R¹⁰, NR¹⁰C(═O)OR²¹, NR¹⁰C(═O)NR¹⁰R¹¹,NR¹⁰SO₂NR¹⁰R¹¹, NR¹⁰SO₂R²¹, S(O)_(p)R¹¹, SO₂NR¹⁰R¹¹, aryl substitutedwith 0-3 groups selected from halogen, C₁-C₄ alkoxy, C₁-C₄ alkyl, CF₃,S(O)_(m)Me, and —NMe₂, aryl(C₁-C₄ alkyl)-, said aryl being substitutedwith 0-3 groups selected from halogen, C₁-₄ alkoxy, C₁-C₄ alkyl, CF₃,S(O)_(p)Me, and —NMe₂, and a 5-10 membered heterocyclic ring containing1-3 N, O, or S heteroatoms, wherein said heterocyclic ring may besaturated, partially saturated, or fully unsaturated, said heterocyclicring being substituted with 0-2 R⁷; R⁷ is selected from: H, hydroxy,C₁-C₄ alkyl, C₁-C₄ alkoxy, aryl, aryl(C₁-C₄ alkyl)-, (C₁-C₄alkyl)carbonyl, CO₂R^(18a), SO₂R¹¹, SO₂NR¹⁰R¹¹, OR¹⁰, and N(R¹¹)R¹²; Uis selected from: —(CH₂)_(n)—, —NH(CH₂)_(n)—, —N(R¹⁰)C(═O)—, and—NHC(═O)(CH₂)_(n); G is N; R⁸ is H; R⁹ is selected from: H, nitro,N(R¹¹)R¹², OC(═O)R¹⁰, OR¹⁰, OC(═O)NR¹⁰R¹¹, NR¹⁰C(═O)R¹⁰, NR¹⁰C(═O)OR²¹,NR¹⁰C(═O)NR¹⁰R¹¹, NR¹⁰SO₂NR¹⁰NR^(1o)SO₂R²¹, hydroxy, OR²², —N(R¹⁰)R¹¹,—N(R¹⁶)R¹⁷, aryl(C₀-C₄ alkyl)carbonyl, aryl(C₁-C₄ alkyl),heteroaryl(C₁-C₄ alkyl), CONR^(18a)R²⁰, SO₂R^(18a) and SO₂NR^(18a)R²⁰,providing that any of the above alkyl, aryl or heteroaryl groups may beunsubstituted or substituted independently with 1-2 R⁷; R¹⁰ is selectedfrom: H, CF₃, C₃-C₆ alkenyl, C₃-C₆ cycloalkyl, aryl, (C₃-C₆cycloalkyl)methyl, aryl(C₁-C₄ alkyl), and C₁-C₄ alkyl substituted with0-2 R⁶; R¹¹ is selected from: <H, hydroxy, C₁-C₄ alkyl, C₃-C₆ alkenyl,C₃-C₆ cycloalkyl, (C₃-C₆ cycloalkyl)methyl, C₁-C₄ alkoxy, benzyloxy,aryl, heteroaryl, heteroaryl(C₁-C₄ akyl)-, aryl(C₁-C₄ alkyl),adamantylmethyl, and C₁-C₄ alkyl substituted with 0-2 R⁴; R¹² isselected from: H, C₁-C₄ alkyl, (C₁-C₄ alkyl)carbonyl, (C₁-C₄alkoxy)carbonyl, phenyl(C₁-C₄ akyl)-, phenylsulfonyl, phenyloxycarbonyl,and phenyl(C₁-C₄ alkoxy)carbonyl, wherein said phenyl groups aresubstituted with 0-2 substituents selected from the group consisting ofC₁-C₄ alkyl, C₁-C₄ alkoxy, halo, CF₃, and nitro; R¹⁶ is selected from:—C(═O)OR^(18a), —C(═O)R^(18b), —C(═O)N(R^(18b))₂, —SO₂R^(18a), and —SO₂N(R^(18b))₂; R¹⁷ is selected from: H, C₁-C₄ alkyl, C₃-C₆ cycloalkyl,C₃-C₆ cycloalkyl(C₁-C₄ akyl)-, aryl, aryl(C₁-C₆ akyl)-, andheteroaryl(C₁-C₆ alkyl); R^(18a) is selected from: C₁-C₄ alkyl, C₃-C₆cycloalkyl, aryl(C₁-C₄ alkyl)-, said aryl substituted with 0-4 R¹⁹,heteroaryl(C₁-C₄ alkyl)-, said heteroaryl substituted with 0-4 R¹⁹,(C₁-C₄ alkyl)heteroaryl, said heteroaryl substituted with 0-4 R¹⁹,heteroaryl substituted with 0-4 R¹⁹, phenyl substituted with 0-4 R¹⁹,and naphthyl substituted with 0-4 R¹⁹; R^(18b) is H or R^(18a); R¹⁹ isselected from: H, halogen, CF₃, CO₂H, CN, NO₂, —NR¹¹R¹², OCF₃, C₁-C₆alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, C₃-C₆cycloalkyl(C₁-C₄ akyl)-, aryl(C₁-C₄ alkyl)-, C₁-C₆ alkoxy, C₁-C₄alkoxycarbonyl, aryl, aryl-O—, aryl-SO₂—, heteroaryl, andheteroaryl-SO₂—, wherein said aryl and heteroaryl groups are substitutedwith 0-4 groups selected from hydrogen, halogen, CF₃, C₁-C₃ alkyl, andC₁-C₃ alkoxy; R²⁰ is selected from: hydroxy, C₁-C₆ alkyloxy, C₃-C₆cycloalkyloxy, aryloxy, aryl(C₁-C₄ alkyl)oxy, C₂-C₁₀alkylcarbonyloxy(C₁-C₂ alkyl)oxy-, C₂-C₁₀ alkoxycarbonyloxy(C₁-C₂alkyl)oxy-, C₂-C₁₀ alkoxycarbonyl(C₁-C₂ alkyl)oxy-, C₃-C₁₀cycloalkylcarbonyloxy(C₁-C₂ alkyl)oxy-, C₃-C₁₀cycloalkoxycarbonyloxy(C₁-C₂ alkyl)oxy-, C₃-C₁₀cycloalkoxycarbonyl(C₁-C₂ alkyl)oxy-, aryloxycarbonyl(C₁-C₂ alkyl)oxy-,aryloxycarbonyloxy(C₁-C₂ alkyl)oxy-, arylcarbonyloxy(C₁-C₂ alkyl)oxy-,C₁-C₅ alkoxy(C₁-C₅ alkyl)carbonyloxy(C₁-C₂ alkyl)oxy-, (5-(C₁-C₅alkyl)-1,3-dioxa-cyclopenten-2-one-yl)methyloxy,(5-aryl-1,3-dioxa-cyclopenten-2-one-yl)methyloxy, and(R¹⁰)(R¹¹)N—(C₁-C₁₀ alkoxy)-; R²¹ is selected from: C₁-C₄ alkyl, C₂-C₆alkenyl, C₃-C₆ cycloalkyl, (C₃-C₆ cycloalkyl)methyl, aryl, aryl(C₁-C₄alkyl)-, and C₁-C₁₀ alkyl substituted with 0-2 R⁷; R²² is selected from:—C(═O) —R^(18b), —C(═O)N(R^(18b))₂, —C(═O)NHSO₂R^(18a),—C(═O)NHC(═O)R^(18b), —C(═O)NHC(═O)OR^(18a), and —C(═O)NHSO₂NHR^(18b); mis 0-2; n is 0-4; and p is 0-2.
 3. A compound of claim 2 of Formula IV:

including stereoisomeric forms thereof, or mixtures of stereoisomericforms thereof, or pharmaceutically acceptable salt forms thereofwherein: R¹ is selected from:

R² and R³ are independently selected from: H, C₁-C₄ alkoxy, NR¹¹R¹²,halogen, NO₂, CN, CF₃, and C₁-C₄ alkyl; R^(2a) is selected from: H,C₁-C₄ alkyl and C₂-C₄ alkenyl; R⁴ is selected from: H, C₁-C₄ alkyl,C₃-C₇ cycloalkyl, C₃-C₇ cycloalkyl(C₁-C₄ alkyl)-, aryl, heteroaryl,aryl(C₁-C₄ alkyl)-, and heteroaryl(C₁-C₄ alkyl)-, wherein said aryl orheteroaryl groups are substituted with 0-2 substituents independentlyselected from the group consisting of C₁-C₄ alkyl, C₁-C₄ alkoxy, F, Cl,Br, CF₃, and NO₂, U is selected from: —(CH₂)_(n)—, —NH(CH₂)_(n)— and—NHC(═O)(CH₂)_(n); R⁸ is H; R⁹ is selected from: H, N(R¹¹)R¹², OR¹⁰,NR¹⁰C(═O)R¹⁰, NR¹⁰SO₂R²¹, —N(R¹⁰)R¹¹, —N(R¹⁶)R¹⁷, aryl(C₀-C₄alkyl)carbonyl, aryl(C₁-C₄ alkyl), heteroaryl(C₁-C₄ alkyl),CONR^(18a)R²⁰, and SO₂NR^(18a)R²⁰; R¹⁰ is selected from: H, CF₃, C₃-C₆alkenyl, C₃-C₆ cycloalkyl, aryl, (C₃-C₆ cycloalkyl)methyl, aryl(C₁-C₄alkyl), and C₁-C₄ alkyl; R¹¹ is selected from: H, hydroxy, C₁-C₄ alkyl,C₃-C₆ alkenyl, C₃-C₆ cycloalkyl, (C₃-C₆ cycloalkyl)methyl, C₁-C₄ alkoxy,benzyloxy, aryl, heteroaryl, heteroaryl(C₁-C₄ akyl)-, aryl(C₁-C₄ alkyl),adamantylmethyl, and C₁-C₄ alkyl substituted with 0-2 R⁴; R¹² isselected from: H, C₁-C₄ alkyl, (C₁-C₄ alkyl)carbonyl, (C₁-C₄alkoxy)carbonyl, phenyl(C₁-C₄ akyl)-, phenylsulfonyl, phenyloxycarbonyl,and phenyl(C₁-C₄ alkoxy)carbonyl, wherein said phenyl groups aresubstituted with 0-2 substituents selected from the group consisting ofC₁-C₄ alkyl, C₁-C₄ alkoxy, halo, CF₃, and nitro; R¹⁶ is selected from:—C(═O)OR^(18a), —C(═O)R^(18b), —C(═O)N(R^(18b))₂, —SO₂R^(18a), and—SO₂N(R^(18b))₂; R¹⁷ is selected from: H and C₁-C₄ alkyl; R^(18a) isselected from: C₁-C₄ alkyl, C₃-C₆ cycloalkyl, aryl(C₁-C₄ alkyl)-, saidaryl substituted with 0-4 R¹⁹, heteroaryl(C₁-C₄ alkyl)-, said heteroarylsubstituted with 0-4 R¹⁹, (C₁-C₄ alkyl)heteroaryl, said heteroarylsubstituted with 0-4 R¹⁹, heteroaryl substituted with 0-4 R¹⁹, phenylsubstituted with 0-4 R¹⁹, and naphthyl substituted with 0-4 R¹⁹; R^(18b)is H or R^(18a); R¹⁹ is selected from: H, halogen, CF₃, CO₂H, CN, NO₂,—NR¹¹R¹², OCF₃, C₁-C₄ alkyl, C₂-C₄ alkenyl, C₂-C₄ alkynyl, C₃-C₆cycloalkyl, C₃-C₆ cycloalkyl(C₁-C₄ akyl)-, aryl(C₁-C₄ akyl)-, C₁-C₄alkoxy, C₁-C₄ alkoxycarbonyl, aryl, aryl—O—, aryl—SO₂-, heteroaryl, andheteroaryl-SO₂—, wherein said aryl and heteroaryl groups are substitutedwith 0-4 groups selected from hydrogen, halogen, CF₃, C₁-C₃ alkyl, andC₁-C₃ alkoxy; R²⁰ is selected from: hydroxy, C₁-C₄ alkyloxy, C₃-C₆cycloalkyloxy, aryloxy, and aryl(C₁-C₄ alkyl)oxy; R²¹ is selected from:C₁-C₄ alkyl, C₂-C₆ alkenyl, C₃-C₆ cycloalkyl, (C₃-C₆ cycloalkyl)methyl,aryl, aryl(C₁-C₄ alkyl)-, and C₁-C₁₀ alkyl substituted with 0-2 R⁷; andn is 0-2.
 4. A compound of claim 3 of Formula IV:

including stereoisomeric forms thereof, or mixtures of stereoisomericforms thereof, or pharmaceutically acceptable salt forms thereofwherein: R¹ is selected from:

R² and R³ are independently selected from: H, methoxy, ethoxy, —NH₂, Br,Cl, F, NO₂, CN, CF₃, methyl and ethyl; R^(2a) is selected from: H,methyl and ethyl; R⁴ is selected from: H, C₁-C₄ alkyl, C₃-C₇ cycloalkyl,C₃-C₇ cycloalkyl(C₁-C₄ akyl)-, aryl, heteroaryl, aryl(C₁-C₄ alkyl)-, andheteroaryl(C_(l)-C₄ alkyl)-, wherein said aryl or heteroaryl groups aresubstituted with 0-2 substituents independently selected from the groupconsisting of C₁-C₄ alkyl, C₁-C₄ alkoxy, F, Cl, Br, CF₃, and NO₂, U is—NHCH₂—; R⁸ is H; R⁹ is selected from: H, OR¹⁰, NR¹⁰SO₂R²¹ and—N(R¹⁶)R¹⁷; R¹⁰ is selected from: H, methyl, ethyl, propyl, butyl,cyclopropyl, cyclopropylmethyl, phenyl and benzyl; R¹⁶ is selected from:—C(═O) R^(18b) , —SO₂R^(18a), and —SO₂N(R^(18b))₂; R¹⁷ is selected from:H, methyl, ethyl, propyl and butyl; R^(18a) is selected from: C₁-C₄alkyl, C₃-C₆ cycloalkyl, aryl(C₁-C₄ alkyl)-, said aryl substituted with0-4 R¹⁹, heteroaryl(C₁-C₄ alkyl)-, said heteroaryl substituted with 0-4R¹⁹, (C₁-C₄ alkyl)heteroaryl, said heteroaryl substituted with 0-4 R¹⁹,heteroaryl substituted with 0-4 R¹⁹, phenyl substituted with 0-4 R¹⁹,and naphthyl substituted with 0-4 R¹⁹; R^(18b) is H or R^(18a); R¹⁹ isselected from: H, halogen, CF₃, CO₂H, CN, NO₂, —NR¹¹R¹², OCF₃, C₁-C₄alkyl, C₂-C₄ alkenyl, C₂-C₄ alkynyl, C₃-C₆ cycloalkyl, C₃-C₆cycloalkyl(C₁-C₄ akyl)-, aryl(C₁-C₄ akyl)-, C₁-C₄ alkoxy, C₁-C₄alkoxycarbonyl, aryl, aryl-O—, aryl—SO₂—, heteroaryl, andheteroaryl-SO₂—, wherein said aryl and heteroaryl groups are substitutedwith 0-4 groups selected from hydrogen, halogen, CF₃, C₁-C₃ alkyl, andC₁-C₃ alkoxy; R²⁰ is selected from: hydroxy, C₁-C₄ alkyloxy, C₃-C₆cycloalkyloxy, aryloxy, and aryl(C₁-C₄ alkyl)oxy; R²¹ is selected from:C₁-C₄ alkyl, C₂-C₆ alkenyl, C₃-C₆ cycloalkyl, (C₃-C₆ cycloalkyl)methyl,aryl, aryl(C₁-C₄ alkyl)-, and C₁-C₁₀ alkyl substituted with 0-2 R⁷.
 5. Acompound of Formula IV:

including stereoisomeric forms thereof, or mixtures of stereoisomericforms thereof, or pharmaceutically acceptable salt forms thereofwherein: R¹ is selected from:

A is —CH₂— or —N(R¹²)—; A¹ and B are independently —CH₂— or —N(R¹⁰)—;l Dis —N(R¹²)— or —S—; E—F is —C (R²)₂C(R³)₂— or —CH(R²)CH(R³)—; R² and R³are independently selected from: H, C₁-C₄ alkoxy, NR¹¹R¹², halogen, NO₂,CN, CF₃, C₁-C₆ alkyl, C₃-C₆ alkenyl, C₃-C₇ cycloalkyl, C₃-C₇cycloalkyl(C₁-C₄ alkyl), aryl(C₁-C₆ alkyl)-, (C₁-C₆ alkyl)carbonyl,(C₁-C₆ alkoxy)carbonyl, arylcarbonyl, and aryl substituted with 0-4 R⁷;alternatively, when R² and R³ are substituents on adjacent atoms, theycan be taken together with the carbon atoms to which they are attachedto form a 5-7 membered carbocyclic or 5-7 membered heterocyclic aromaticor nonaromatic ring system, said carbocyclic or heterocyclic ring beingsubstituted with 0-2 groups selected from C₁-C₄ alkyl, C₁-C₄ alkoxy,halo, cyano, amino, CF₃ and NO₂; R^(2a) is selected from: H, C₁-C₁₀alkyl, C₂-C₆ alkenyl, C₃-C₁₁ cycloalkyl, C₃-C₇ cycloalkyl(C₁-C₄ alkyl),aryl, aryl(C₁-C₄ alkyl)-, (C₂-C₇ alkyl)carbonyl, arylcarbonyl, (C₂-C₁₀alkoxy)carbonyl, C₃-C₇ cycloalkoxycarbonyl, C₇-C₁₁bicycloalkoxycarbonyl, aryloxycarbonyl, aryl(C₁-C₁₀ alkoxy)carbonyl,C₁-C₆ alkylcarbonyloxy(C₁-C₄ alkoxy)carbonyl, arylcarbonyloxy(C₁-C₄alkoxy)carbonyl, and C₃-C₇ cycloalkylcarbonyloxy(C₁-C₄ alkoxy)carbonyl;R⁴ is selected from: H, C₁-C₆ alkyl, C₃-C₇ cycloalkyl, C₃-C₇cycloalkyl(C₁-C₄ akyl)-, aryl, heteroaryl, aryl(C₁-C₆ alkyl)-, andheteroaryl(C₁-C₆ alkyl)-, wherein said aryl or heteroaryl groups aresubstituted with 0-2 substituents independently selected from the groupconsisting of C₁-C₄ alkyl, C₁-C₄ alkoxy, F, Cl, Br, CF₃, and NO₂; R⁶ isselected from: H, C₁-C₁₀ alkyl, hydroxy, C₁-C₁₀ alkoxy, nitro, C₁-C₁₀alkylcarbonyl, —N(R¹¹)R¹², cyano, halo, CF₃, CHO, CO₂R^(18b),C(═O)R^(18b), CONR¹⁷R^(18b), OC(═O)R¹⁰, OR¹⁰, OC(═O)NR¹⁰R¹¹,NR¹⁰C(═O)R¹⁰, NR¹⁰C(═O)OR²¹, NR¹⁰C(═O)NR¹⁰R¹¹, NR¹⁰SO₂NR¹⁰R¹¹,NR¹⁰SO₂R²¹, S(O)_(p)R¹¹, SO₂NR¹⁰R¹¹, aryl substituted with 0-3 groupsselected from halogen, C₁-C₆ alkoxy, C₁-C₆ alkyl, CF₃, S(O)_(m)Me, and—NMe₂, aryl(C₁-C₄ alkyl)-, said aryl being substituted with 0-3 groupsselected from halogen, C₁-C₆ alkoxy, C₁-C₆ alkyl, CF₃, S(O)_(p)Me, and—NMe₂, and a 5-10 membered heterocyclic ring containing 1-3 N, O, or Sheteroatoms, wherein said heterocyclic ring may be saturated, partiallysaturated, or fully unsaturated, said heterocyclic ring beingsubstituted with 0-2 R⁷; R⁷ is selected from: H, hydroxy, C₁-C₄ alkyl,C₁-C₄ alkoxy, aryl, aryl(C₁-C₄ alkyl)-, (C₁-C₄ alkyl)carbonyl,CO₂R^(18a), SO₂R¹¹, SO₂NR¹⁰R¹¹, OR¹⁰, and N(R¹¹)R¹²; U is selected from:—(CH₂)_(n)—, —(CH₂)_(n)O(CH₂)_(m), —NH(CH₂)_(n)—, —N(R¹⁰)C(═O)—,—NHC(═O)(CH₂)_(n)—, and —C(═O)N(R¹⁰)—; G is N; R⁸ is selected from: H,CO₂R^(18b), C(═O)R^(18b), CON¹⁷R^(18b), C₁-C₁₀ alkyl substituted with0-1 R⁶, C₂-C₁₀ alkenyl substituted with 0-1 R⁶, C₂-C₁₀ alkynylsubstituted with 0-1 R⁶, C₃-C₈ cycloalkyl substituted with 0-1 R⁶, C₅-C₆cycloalkenyl substituted with 0-1 R⁶, (C₁-C₁₀ alkyl)carbonyl, C₃-C₁₀cycloalkyl(C₁-C₄ alkyl)-, phenyl substituted with 0-3 R⁶, naphthylsubstituted with 0-3 R⁶, a 5-10 membered heterocyclic ring containing1-3 N, O, or S heteroatoms, wherein said heterocyclic ring may besaturated, partially saturated, or fully unsaturated, said heterocyclicring being substituted with 0-2 R⁷; R⁹ is selected from: C₁-C₁₀ alkylsubstituted with 0-1 R⁶, C₁-C₁₀ alkoxy substituted with 0-2 R⁷, H,nitro, N(R¹¹)R¹², OC(═O)R¹⁰, OR¹⁰, OC(═O)NR¹⁰R¹¹, NR¹⁰C(═O)R¹⁰,NR¹⁰C(═O)OR²¹, NR¹⁰C(═O)NR¹⁰R¹¹, NR¹⁰SO₂NR¹⁰R¹¹, NR¹⁰SO₂R²¹, hydroxy,OR²², —N(R¹⁰)R¹¹, —N(R¹⁶)R¹⁷, aryl(C₀-C₆ alkyl)carbonyl, aryl(C₁-C₆alkyl), heteroaryl(C₁-C₆ alkyl), CONR^(18a)R²⁰, SO₂R^(18a), andSO₂NR^(18a)R²⁰, providing that any of the above alkyl, aryl orheteroaryl groups may be unsubstituted or substituted independently with1-2 R⁷; R¹⁰ is selected from: H, CF₃, C₃-C₆ alkenyl, C₃-C₁₁ cycloalkyl,aryl, (C₃-C₁₁ cycloalkyl)methyl, aryl(C₁-C₄ alkyl), and C₁-C₁₀ alkylsubstituted with 0-2 R⁶; R¹¹ is selected from: H, hydroxy, C₁-C₈ alkyl,C₃-C₆ alkenyl, C₃-C₁₁ cycloalkyl, (C₃-C₁₁ cycloalkyl)methyl, C₁-C₆alkoxy, benzyloxy, aryl, heteroaryl, heteroaryl(C₁-C₄ akyl)-, aryl(C₁-C₄alkyl), adamantylmethyl, and C₁-C₁₀ alkyl substituted with 0-2 R⁴; R¹²is selected from: H, C₁-C₆ alkyl, triphenylmethyl, methoxymethyl,methoxyphenyldiphenylmethyl, trimethylsilylethoxymethyl, (C₁-C₆alkyl)carbonyl, (C₁-C₆ alkoxy)carbonyl, (C₁-C₆ alkyl)aminocarbonyl,C₃-C₆ alkenyl, C₃-C₇ cycloalkyl, C₃-C₇ cycloalkyl(C₁-C₄ akyl)-, aryl,heteroaryl(C₁-C₆ alkyl)carbonyl, heteroarylcarbonyl, aryl(C₁-C₆ alkyl)-,(C₁-C₆ alkyl)carbonyl, arylcarbonyl, C₁-C₆ alkylsulfonyl, arylsulfonyl,aryl(C₁-C₆ alkyl)sulfonyl, heteroarylsulfonyl, heteroaryl(C₁-C₆alkyl)sulfonyl, aryloxycarbonyl, and aryl(C₁-C₆ alkoxy)carbonyl, whereinsaid aryl groups are substituted with 0-2 substituents selected from thegroup consisting of C₁-C₄ alkyl, C₁-C₄ alkoxy, halo, CF₃, and nitro; R¹⁶is selected from: —C(═O)OR^(18a), —C(═O)R^(18b), —C(═O)N(R^(18b))₂,—C(═O)NHSO₂R^(18a), —C(═O)NHC(═O)R^(18b), —C(═O)NHC(═O)OR^(18a),—C(═O)NHSO₂NHR^(18b), —SO₂R^(18a), —SO₂N(R^(18b))₂, and—SO₂NHC(═O)OR^(18b); R¹⁷ is selected from: H, C₁-C₆ alkyl, C₃-C₇cycloalkyl, C₃-C₇ cycloalkyl(C₁-C₄ akyl)-, aryl, aryl(C₁-C₆ alkyl)-, andheteroaryl(C₁-C₆ alkyl); R^(18a) is selected from: C₁-C₈ alkyl, C₃-C₁₁cycloalkyl, aryl(C₁-C₆ alkyl)-, said aryl substituted with 0-4 R¹⁹,heteroaryl(C₁-C₆ alkyl)-, said heteroaryl substituted with 0-4 R¹⁹,(C₁-C₆ alkyl)heteroaryl, said heteroaryl substituted with 0-4 R¹⁹,heteroaryl substituted with 0-4 R¹⁹, phenyl substituted with 0-4 R¹⁹,and naphthyl substituted with 0-4 R¹⁹; R^(18b) is H or R^(18a); R¹⁹ isselected from: H, halogen, CF₃, CO₂H, CN, NO₂, —NR¹¹R¹², OCF₃, C₁-C₈alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₁₁ cycloalkyl, C₃-C₇cycloalkyl(C₁-C₄ alkyl)-, aryl(C₁-C₆ alkyl)-, C₁-C₆ alkoxy, C₁-C₄alkoxycarbonyl, aryl, aryl-O—, aryl-SO₂—, heteroaryl, andheteroaryl-SO₂—, wherein said aryl and heteroaryl groups are substitutedwith 0-4 groups selected from hydrogen, halogen, CF₃, C₁-C₃ alkyl, andC₁-C₃ alkoxy; R²⁰ is selected from: hydroxy, C₁-C₁₀ alkyloxy, C₃-C₁₁cycloalkyloxy, aryloxy, aryl(C₁-C₄ alkyl)oxy, C₂-C₁₀alkylcarbonyloxy(C₁-C₂ alkyl)oxy-, C₂-C₁₀ alkoxycarbonyloxy(C₁-C₂alkyl)oxy-, C₂-C₁₀ alkoxycarbonyl(C₁-C₂ alkyl)oxy-, C₃-C₁₀cycloalkylcarbonyloxy(C₁-C₂ alkyl)oxy-, C₃-C₁₀cycloalkoxycarbonyloxy(C₁-C₂ alkyl)oxy-, C₃-C₁₀cycloalkoxycarbonyl(C₁-C₂ alkyl)oxy-, aryloxycarbonyl(C₁-C₂ alkyl)oxy-,aryloxycarbonyloxy(C₁-C₂ alkyl)oxy-, arylcarbonyloxy(C₁-C₂ alkyl)oxy-,C₁-C₅ alkoxy(C₁-C₅ alkyl)carbonyloxy(C₁-C₂ alkyl)oxy-, (5-(C₁-C₅alkyl)-1,3-dioxa-cyclopenten-2-one-yl)methyloxy,(5-aryl-1,3-dioxa-cyclopenten-2-one-yl)methyloxy, and(R¹⁰)(R¹¹)N—(C₁-C₁₀ alkoxy)-; R²¹ is selected from: C₁-C₈ alkyl, C₂-C₆alkenyl, C₃-C₁₁ cycloalkyl, (C₃-C₁₁ cycloalkyl)methyl, aryl, aryl(C₁-C₄alkyl)-, and C₁-C₁₀ alkyl substituted with 0-2 R⁷; R²² is selected from:—C(═O)R^(18b), —C(═O)N(R^(18b))₂, —C(═O)NHSO₂R^(18a),—C(═O)NHC(═O)R^(18b), and —C(═O)NHC(═O)OR^(18a); m is 0-2; n is 0-4; pis 0-2; and r is 0-2; with the proviso that n and m are chosen such thatthe number of atoms connecting R¹ and COR²⁰ of Formula (IV) is in therange of 10-14.
 6. A compound of claim 5 of Formula IV:

including stereoisomeric forms thereof, or mixtures of stereoisomericforms thereof, or pharmaceutically acceptable salt forms thereofwherein: R¹ is selected from:

D is —N(R¹²)— or —S—; E—F is —C(R²)₂C(R³)₂— or —CH(R²)CH(R³)—; R² and R³are independently selected from: H, C₁-C₄ alkoxy, NR¹¹R¹², halogen, NO₂,CN, CF₃, C₁-C₆ alkyl, C₃-C₆ alkenyl, C₃-C₇ cycloalkyl, C₃-C₇cycloalkyl(C₁-C₄ alkyl), aryl(C₁-C₆ alkyl)-, (C₁-C₆ alkyl)carbonyl,(C₁-C₆ alkoxy)carbonyl, arylcarbonyl, and aryl substituted with 0-4 R⁷,alternatively, when R² and R³ are substituents on adjacent atoms, theycan be taken together with the carbon atoms to which they are attachedto form a 5-7 membered carbocyclic or 5-7 membered heterocyclic aromaticor nonaromatic ring system, said carbocyclic or heterocyclic ring beingsubstituted with 0-2 groups selected from C₁-C₄ alkyl, C₁-C₄ alkoxy,halo, cyano, amino, CF₃ and NO₂; R^(2a) is selected from: H, C₁-C₁₀alkyl, C₂-C₆ alkenyl, C₃-C₁₁ cycloalkyl, C₃-C₇ cycloalkyl(C₁-C₄ alkyl),aryl, aryl(C₁-C₄ alkyl)-, (C₂-C₇ alkyl)carbonyl, arylcarbonyl, (C₂-C₁₀alkoxy)carbonyl, C₃-C₇ cycloalkoxycarbonyl, C₇-C₁₁bicycloalkoxycarbonyl, aryloxycarbonyl, aryl(C₁-C₁₀ alkoxy)carbonyl,C₁-C₆ alkylcarbonyloxy(C₁-C₄ alkoxy)carbonyl, arylcarbonyloxy(C₁-C₄alkoxy)carbonyl, and C₃-C₇ cycloalkylcarbonyloxy(C₁-C₄ alkoxy)carbonyl;R⁴ is selected from: H, C₁-C₆ alkyl, C₃-C₇ cycloalkyl, C₃-C₇cycloalkyl(C₁-C₄ akyl)-, aryl, heteroaryl, aryl(C₁-C₆ alkyl)-, andheteroaryl(C₁-C₆ alkyl)-, wherein said aryl or heteroaryl groups aresubstituted with 0-2 substituents independently selected from the groupconsisting of C₁-C₄ alkyl, C₁-C₄ alkoxy, F, Cl, Br, CF₃, and NO₂, R⁶ isselected from: H, C₁-C₁₀ alkyl, hydroxy, C₁-C₁₀ alkoxy, nitro, C₁-C₁₀alkylcarbonyl, —N(R¹¹)R¹², cyano, halo, CF₃, CHO, CO₂R^(18b),C(═O)R^(18b), CONR¹⁷R^(18b), OC(═O)R¹⁰, OR¹⁰, OC(═O)NR¹⁰R¹¹,NR¹⁰C(═O)R¹⁰, NR¹⁰C(═O)OR²¹, NR¹⁰C(═O)NR¹⁰OR¹¹, NR¹⁰SO₂NR¹⁰R¹¹,NR¹⁰SO₂R²¹, S(O)_(p)R¹¹, SO₂NR¹⁰R¹¹, aryl substituted with 0-3 groupsselected from halogen, C₁-C₆ alkoxy, C₁-C₆ alkyl, CF₃, S(O)_(m)Me, and—NMe₂, aryl(C₁-C₄ alkyl)-, said aryl being substituted with 0-3 groupsselected from halogen, C₁-C₆ alkoxy, C₁-C₆ alkyl, CF₃, S(O)_(p)Me, and—NMe₂, and a 5-10 membered heterocyclic ring containing 1-3 N, O, or Sheteroatoms, wherein said heterocyclic ring may be saturated, partiallysaturated, or fully unsaturated, said heterocyclic ring beingsubstituted with 0-2 R⁷; R⁷ is selected from: H, hydroxy, C₁-C₄ alkyl,C₁-C₄ alkoxy, aryl, aryl(C₁-C₄ alkyl)-, (C₁-C₄ alkyl)carbonyl,CO₂R^(18a), SO₂R¹¹, SO₂NR¹⁰R¹¹, OR¹⁰, and N(R¹¹)R¹²; U is selected from:—(CH₂)_(n)—, —(CH₂)_(n)O(CH₂)_(m)—, —NH(CH₂)_(n)—, —N(R¹⁰)C(═O)—,—NHC(═O)(CH₂)_(n)—, and —C(═O)N(R¹⁰)—; G is N; R⁸ is H; R⁹ is selectedfrom: H, nitro, N(R¹¹)R¹², OC(═O)R¹⁰, OR¹⁰, OC(═O)NR¹⁰R¹¹, NR¹⁰C(═O)R¹⁰,NR¹⁰C(═O)OR²¹, NR¹⁰C(═O)NR¹⁰OR¹¹, NR¹⁰SO₂NR¹⁰R¹¹, NR¹⁰SO₂R²¹, hydroxy,OR²², —N(R¹⁰)R¹¹, —N(R¹⁶)R¹⁷, aryl(C₀-C₆ alkyl)carbonyl, aryl(C₁-C₆alkyl), heteroaryl(C₁-C₆ alkyl), CONR^(18a)R²⁰, SO₂R^(18a), andSO₂NR^(18a)R²⁰, providing that any of the above alkyl, aryl orheteroaryl groups may be unsubstituted or substituted independently with1-2 R⁷; R¹⁰ is selected from: H, CF₃, C₃-C₆ alkenyl, C₃-C₁₁ cycloalkyl,aryl, (C₃-C₁₁ cycloalkyl)methyl, aryl(C₁-C₄ alkyl), and C₁-C₁₀ alkylsubstituted with 0-2 R⁶; R¹¹is selected from: H, hydroxy, C₁-C₈ alkyl,C₃-C₆ alkenyl, C₃-C₁₁ cycloalkyl, (C₃-C₁₁ cycloalkyl)methyl, C₁-C₆alkoxy, benzyloxy, aryl, heteroaryl, heteroaryl(C₁-C₄ akyl)-, aryl(C₁-C₄alkyl), adamantylmethyl, and C₁-C₁₀ alkyl substituted with 0-2 R⁴; R¹²is selected from: H, C₁-C₄ alkyl, (C₁-C₄ alkyl)carbonyl, (C₁-C₄alkoxy)carbonyl, phenyl(C₁-C₄ akyl)-, phenylsulfonyl, phenyloxycarbonyl,and phenyl(C₁-C₄ alkoxy)carbonyl, wherein said phenyl groups aresubstituted with 0-2 substituents selected from the group consisting ofC₁-C₄ alkyl, C₁-C₄ alkoxy, halo, CF₃, and nitro; R¹⁶ is selected from:—C(═O)OR^(18a), —C(═O)R^(18b), —C(═O)N(R^(18b))₂, —C(═O)NHSO₂R^(18a),—C(═O)NHC(═O)R^(18b), —C(═O)NHC(═O)OR^(18a), —C(═O)NHSO₂NHR^(18b),—SO₂R^(18a), —SO₂N(R^(18b))₂, and —SO₂NHC (═O) OR^(18b); R¹⁷ is selectedfrom: H, C₁-C₆ alkyl, C₃-C₇ cycloalkyl, C₃-C₇ cycloalkyl(C₁-C₄ akyl)-,aryl, aryl(C₁-C₆ alkyl)-, and heteroaryl(C₁-C₆ alkyl); R^(18a) isselected from: C₁-C₈ alkyl, C₃-C₁₁ cycloalkyl, aryl(C₁-C₆ alkyl)-, saidaryl substituted with 0-4 R¹⁹, heteroaryl(C₁-C₆ alkyl)-, said heteroarylsubstituted with 0-4 R¹⁹, (C₁-C₆ alkyl)heteroaryl, said heteroarylsubstituted with 0-4 R¹⁹, heteroaryl substituted with 0-4 R¹⁹, phenylsubstituted with 0-4 R¹⁹, and naphthyl substituted with 0-4 R¹⁹; R^(18b)is H or R^(18a); R¹⁹ is selected from: H, halogen, CF₃, CO₂H, CN, NO₂,—NR¹¹R¹², OCF₃, C₁-C₈ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₁₁cycloalkyl, C₃-C₇ cycloalkyl(C₁-C₄ alkyl)-, aryl(C₁-C₆ alkyl)-, C₁-C₆alkoxy, C₁-C₄ alkoxycarbonyl, aryl, aryl—O—, aryl—SO₂—, heteroaryl, andheteroaryl-SO₂—, wherein said aryl and heteroaryl groups are substitutedwith 0-4 groups selected from hydrogen, halogen, CF₃, C₁-C₃ alkyl, andC₁-C₃ alkoxy; R²⁰ is selected from: hydroxy, C₁-C₁₀ alkyloxy, C₃-C₁₁cycloalkyloxy, aryloxy, aryl(C₁-C₄ alkyl)oxy, C₂-C₁₀alkylcarbonyloxy(C₁-C₂ alkyl)oxy-, C₂-C₁₀ alkoxycarbonyloxy(C₁-C₂alkyl)oxy-, C₂-C₁₀ alkoxycarbonyl(C₁-C₂ alkyl)oxy-, C₃-C₁₀cycloalkylcarbonyloxy(C₁-C₂ alkyl)oxy-, C₃-C₁₀cycloalkoxycarbonyloxy(C₁-C₂ alkyl)oxy-, C₃-C₁₀cycloalkoxycarbonyl(C₁-C₂ alkyl)oxy-, aryloxycarbonyl(C₁-C₂ alkyl)oxy-,aryloxycarbonyloxy(C₁-C₂ alkyl)oxy-, arylcarbonyloxy(C₁-C₂ alkyl)oxy-,C₁-C₅ alkoxy(C₁-C₅ alkyl)carbonyloxy(C₁-C₂ alkyl)oxy-, (5-(C₁-C₅alkyl)-1,3-dioxa-cyclopenten-2-one-yl)methyloxy,(5-aryl-1,3-dioxa-cyclopenten-2-one-yl)methyloxy, and(R¹⁰)(R¹¹)N—(C₁-C₁₀ alkoxy)-; R²¹ is selected from: C₁-C₈ alkyl, C₂-C₆alkenyl, C₃-C₁₁ cycloalkyl, (C₃-C₁₁ cycloalkyl)methyl, aryl, aryl(C₁-C₄alkyl)-, and C₁-C₁₀ alkyl substituted with 0-2 R⁷; R²² is selected from:—C(═O)R^(18b), —C(═O)N(R^(18b))₂, —C(═O)NHSO₂R^(18a),—C(═O)NHC(═O)R^(18b), and —C(═O)NHC(═O)OR^(18a); m is 0-2; n is 0-4; pis 0-2; and with the proviso that n and m are chosen such that thenumber of atoms connecting R¹ and COR²⁰ of Formula (IV) is in the rangeof 10-14.
 7. A pharmaceutical composition comprising a pharmaceuticallyacceptable carrier and a compound of claim
 1. 8. A pharmaceuticalcomposition comprising a pharmaceutically acceptable carrier and acompound of claim
 2. 9. A pharmaceutical composition comprising apharmaceutically acceptable carrier and a compound of claim
 3. 10. Apharmaceutical composition comprising a pharmaceutically acceptablecarrier and a compound of claim
 4. 11. A pharmaceutical compositioncomprising a pharmaceutically acceptable carrier and a compound of claim5.
 12. A pharmaceutical composition comprising a pharmaceuticallyacceptable carrier and a compound of claim
 6. 13. A method for thetreatment of cancer metastasis, diabetic retinopathy, neovascularglaucoma, thrombosis, restenosis, osteoporosis, or macular degenerationwhich comprises administering to a host in need of such treatment atherapeutically effective amount of a compound of claim
 1. 14. A methodfor the treatment of cancer metastasis, diabetic retinopathy,neovascular glaucoma, thrombosis, restenosis, osteoporosis, or maculardegeneration which comprises administering to a host in need of suchtreatment a therapeutically effective amount of a compound of claim 2.15. A method for the treatment of cancer metastasis, diabeticretinopathy, neovascular glaucoma, thrombosis, restenosis, osteoporosis,or macular degeneration which comprises administering to a host in needof such treatment a therapeutically effective amount of a compound ofclaim
 3. 16. A method for the treatment of cancer metastasis, diabeticretinopathy, neovascular glaucoma, thrombosis, restenosis, osteoporosis,or macular degeneration which comprises administering to a host in needof such treatment a therapeutically effective amount of a compound ofclaim
 4. 17. A method for the treatment of cancer metastasis, diabeticretinopathy, neovascular glaucoma, thrombosis, restenosis, osteoporosis,or macular degeneration which comprises administering to a host in needof such treatment a therapeutically effective amount of a compound ofclaim
 5. 18. A method for the treatment of cancer metastasis, diabeticretinopathy, neovascular glaucoma, thrombosis, restenosis, osteoporosis,or macular degeneration which comprises administering to a host in needof such treatment a therapeutically effective amount of a compound ofclaim 6.